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Faculty of Science
Bachelor Chemistry
Hydrolyzed Phosphite as a Constructive Tool for Hydrogen Bonded Bidentate
Ligands in Homogeneous Catalysis
How to make your nasty side-products useful
Evi Van Acker
0365734
Bachelor Project
Prof. Dr. J.N.H.Reek
Ir. J. Meeuwissen
Amsterdam
November 17th, 2006
Abstract
The need to synthesize enantiopure compounds rapidly and inexpensively is ever-increasing.
Enormous efforts are being made to develop new and improved catalytic systems. A method in
which very large numbers of chemical entities are synthesized by condensing a small number of
reagents in all possible combinations defined by a small set of reactions, describes the essence of
combinatorial chemistry. In this field of chemistry, it is the objective to make an array of
chemical compounds – so called libraries – that can be screened efficiently for the identification
of useful compounds.
Supramolecular chemistry focuses on the non-covalent bonding interactions of molecules.
Important concepts that have been demonstrated by this type of chemistry include host-guest
chemistry, self-assembly and molecular recognition, but recently it has found its applications in
transition-metal catalysis. Catalysts can be generated rapidly and selectively in a synthesis robot
by means of supramolecular interactions and the catalytic process can be monitored using ultrafast chiral gas chromatography.
In this project (S)-2,2’-binaphtyl phosphite was synthesized and the goal was set to generate
hydrogen-bonded hetero-complexes with this ligand for rhodium catalyzed asymmetric
hydrogenation reactions. Metal-complex NMR studies were performed with platinum and
rhodium precursors to gain more insight in the behavior and the formation of complexes possibly
stabilized through hydrogen bonding. Remarkable shifts were seen in the P31-NMR of the
rhodium complexes upon the addition of 1 equivalent of Et3N. In a synthesis robot, (S)-2,2’binaphtyl phosphite was used to generate homo-combinations and the effect of base addition was
tested in four asymmetric hydrogenation reactions. In the asymmetric hydrogenation of dimethyl
itaconate the enantioselectivity was improved from 57 % to 79.6 % ee when 2 equivalents of Et3N
were added. The same trend, though less remarkable, was seen with other substrates upon the
addition of 1 equivalent of base. These hydrogen bonded bidentate complexes have great
potential as a new class of ligands for asymmetric hydrogenation reactions. If the heterocombinations show higher selectivity than the homo-combinations, it will lead to a better result of
the reaction as a whole. (S)-2,2’-binaphtyl phosphite was combined with proper ligands to
generate hetero-complexes, but these did not show significant higher selectivity than their homocombinations in the asymmetric hydrogenation reactions.
2
Samenvatting
De vraag naar snelle en goedkope syntheseroutes voor enantiozuivere producten wordt steeds
groter. De ontwikkeling van nieuwe en verbeterde katalytische systemen is daarom het doel van
menig chemici. Een methode waarin uitgaand van een beperkte hoeveelheid uitgangsstoffen, een
groot aantal moleculen gesynthetiseerd wordt in allerlei mogelijke combinaties die vastgelegd
zijn door een klein aantal reacties, vormt de kern van de combinatie chemie. Hierin wordt
getracht een scala aan componenten te maken, zogenaamde bibliotheken, die efficiënt gescreend
kunnen worden voor het ontdekken van nieuwe en nuttige producten.
Supramoleculaire chemie beschrijft de niet-covalente bindingsinteracties van moleculen. De
potentie van deze chemie werd al eerder aangetoond in de host-guest chemie en het zelf
assembleren van membranen. Het is pas recent dat de supramoleculaire chemie haar toepassingen
heeft gevonden in de overgangsmetaal katalyse. Katalysatoren kunnen snel en selectief
gegenereerd worden in een syntheserobot door middel van supramoleculaire interacties. Het
katalytische proces kan gevolgd worden met chirale gas chromatografie.
In dit project werd het (S)-2,2’-binaphtyl fosfiet ligand gesynthetiseerd. Speciale interesse ging
uit naar het vormen van waterstof gebonden complexen met dit ligand voor rhodium
gekatalyseerde asymmetrische hydrogenerings reacties. Om meer inzicht te krijgen in het gedrag
en het ontstaan van complexen die mogelijk gestabiliseerd worden door waterstof bruggen,
werden NMR studies gedaan met platinum en rhodium precursors. Opmerkelijke verschuivingen
werden waargenomen in het P31-NMR van de rhodium complexen bij het toevoegen van 1
equivalent Et3N. In een syntheserobot werd het (S)-2,2’-binaphtyl fosfiet ligand gebruikt voor het
vormen van homocomplexen waarbij het effect van de base getest werd in vier asymmetrische
hydrogenerings reacties. In de hydrogenering van dimethyl itaconate steeg de enantiomere
overmaat van 57 % naar 79.6 % bij een toevoeging van 2 equivalent Et 3N. Dezelfde trend werd
waargenomen bij de andere substraten bij een toevoeging van 1 equivalent base, hoewel deze
minder significant was. (S)-2,2’-binaphtyl fosfiet werd gecombineerd met verschillende liganden
om heterocomplexen te maken. Deze waterstof gebonden bidentaat complexen hebben veel
potentie als een nieuwe klasse liganden voor asymmetriche hydrogenerings reacties. Als de
heterocombinatie selectiever is dan de homocombinatie dan zal dat tot een beter resultaat leiden
voor de reactie als geheel. (S)-2,2’-binaphtyl fosfiet werd gecombineerd met verschillende
liganden om heterocomplexen te maken. Jammer genoeg vertoonden deze geen duidelijke
verbetering in enantioselectiviteit ten opzichte van de homocombinaties.
3
Table of Contents
1. Introduction
5
1.1 Strive to Perfection
5
1.2 Homogeneous Asymmetric Catalysis
5
1.3 Monodentate Phosphorus Ligands
6
1.4 Combinatorial Asymmetric Catalysis: The Power is in the Numbers
7
1.5 Monodentate Ligand Combination Approach
8
1.6 Supramolecular Strategies in Combinatorial Asymmetric Catalysis
9
1.7 Project Goal
2. Results and Discussion
10
11
2.1 Synthesis of (S)-2,2’-binaphtyl phosphite
11
2.2 Metal-complex NMR Studies
13
2.2.1 Platinum Complexes: Pt(PPh3)4 as Metal Precursor
13
2.2.2 Platinum Complexes: Pt(PPh3)2Cl2 as Metal Precursor
14
2.2.2 Rhodium Complexes: Rh(nbd)2BF4 as Metal Precursor
17
2.3 Rhodium Catalyzed Asymmetric Hydrogenation Reactions
2.3.1 Homo-complexes with (S)-2,2’-binaphtyl phosphite
19
19
and the Effect of Base Addition
2.3.2 Hetero-complexes with (S)-2,2’-binaphtyl phosphite
22
3. Conclusions and Future Work
25
4. Experimental Section
26
5. References
27
4
1. Introduction
1.1 Strive to Perfection
Chemical industries are concerned about the disposing of unwanted side-products and the
expense of inefficiency of chemical processes. Developing a method that allows the selective
production of one enantiomer in favor of the other, is a goal set by many chemists, especially in
the field of homogeneous catalysis. The ability to produce enantiopure compounds in large
quantities is necessary, especially in a world where the demand for intermediates and products
with enantiomeric excess of more then 99% is ever-increasing. Enormous efforts are being made
for the development of new and improved catalytic systems.
1.2 Homogeneous Asymmetric Catalysis
Hydrogenation reactions are widely used and are of great importance in many fields of chemistry.
In this type of reaction, an unsaturated bond is reduced to a saturated bond, through the addition
of hydrogen. In the early sixties it was not known, whether catalytic asymmetric hydrogenation
reactions were feasible. In a catalytic asymmetric reaction a chiral catalyst – containing a chiral
group or ligand – is used to generate large quantities of an optically active compound from a
chiral or an achiral precursor. In 1966 J. A. Osborn and G. Wilkinson had published their
discovery on the rhodium complex RhCl(PPh3)3 which was able to reduce unhindered alkenes
with molecular hydrogen in a controlled fashion and under mild conditionsi. The question if it
would be possible to catalyze an asymmetric reaction to produce an excess of one of the
enantiomers, remained unanswered, until W. S. Knowles came with a breakthrough in 1968ii.
Knowles used a transition metal to generate a chiral catalyst that could transfer chirality to an
achiral substrate resulting in a chiral product with one of the enantiomers in excess. He modified
Wilkinson’s homogeneous hydrogenation catalyst with a chiral monodentate phosphane, which
led to a chiral homogeneous catalyst for the hydrogenation of prochiral olefins. The effect of this
approach was tested in a pioneering experiment where α-phenylacrylic (1) acid was hydrogenated
using such a modified catalyst (3) (Scheme 1). Although the original enantioselectivities were
low, it was great proof of principle.
CO2H
CO2H
I
Pr
cat Rh., L, H2
PPh2
P
Me
1
O
2
Ph
3
(e.e. = 15%)
PPh2
O
4
(e.e. = 63 %)
Scheme 1. The comparison of mono- and bidentate in asymmetric hydrogenation of α-phenylacrylic
5
The low enantioselectivities were attributed to the many degrees of freedom of the rhodium
complexes. Particularly the rotation around the rhodium-phosphor bond was considered to be of
major importance. Knowing this, Kagan made an important contribution synthesizing DIOP (4),
the first chiral bidentate phosphane ligand, and it proved to be an effective ligand in increasing
the enantioselectivity of the catalyst (Scheme 1, 4)iii. This set the standard for the development of
chiral ligands for asymmetric hydrogenations, leading to privileged bidentate ligands such as
DuPHosiv (5) and BINAPv (6), which form the basis for highly enantioselective catalysts (Figure
1).
PPh2
P
PPh2
P
(S,S)-DuPHOS
(S)-BINAP 6
5
Figure 1. DuPHos and BINAP as examples of bidentate ligands in asymmetric hydrogenation reactions
1.3 Monodentate Phosphorus Ligands
Considering the tremendous accomplishments, the field was soon taken over by chiral bidentate
phosphorus ligands and for more than thirty years hundreds of these ligands were developed on
the basis of the assumption that they were necessary to achieve high enantioselectivities in
hydrogenation reactions. However, there is no mechanistic theory, which excludes monodentate
ligands from giving efficient asymmetric catalysis. It came as a complete surprise that
monodentate BINOL-based phosphoramidites (7), phosphonites (8), phosphites (9) and
phosphines gave enantioselectivities up to 99 % in the catalytic hydrogenation of 2-methylacetamido acrylate (Scheme 2)vi.
CO2Me
CO2Me
Rh(COD)2BF4, L
H2
H
NHAc
NHAc
O
O
7
R
P
N
R
O
O
P
8
R
O
O
P
OR
9
6
Scheme 2. Monodentate ligands used in asymmetric hydrogenation reactions
It seemed that monodentate gave similar or sometimes even better results than bidentate ligands,
but their relative simple synthesis, modular structure and low cost, make them very attractive for
applications in asymmetric catalysis. Furthermore they have the ability to favor substrate
coordination, stabilize intermediates and provide selectivity through steric effects. From a
preparative viewpoint, one problem remains: they are susceptible to oxidation and, or hydrolysis,
which is not exactly an advantage for routine use and scale up.
It was found in literature that the most versatile chiral monodentate ligands used in the
asymmetric hydrogenation of functionalized alkenes are phosphoramidites and phosphites based
on atropisomeric BINOL (10) as the backbone. The use of monodentate phosphites as ligands in
rhodium – catalyzed asymmetric hydrogenation was discovered by Reetz et al vii.
Phosphoramidites (12) as well as phosphites (13) can be synthesized through the same
phosphochlorite (11) intermediate, after the addition of an amine or an alcohol respectively
(Scheme 3). This synthesis offers a great chance to tune the ligands considering the large amount
of amines and alcohols available. The high levels of stereo-control exerted by these ligands in
combination with their facile synthesis and modular structure puts them among the most
privileged ligands for asymmetric catalysis.
12
R1
HNR1R2
Et3N
PCl3
O
OH reflux
O
OH
P
11
O
P
N
R2
Cl
Et3N
10
O
HOR
O
O
P
OR
13
Scheme 3. Synthesis of monodentate phosphoramidites and phosphites
1.4 Combinatorial Asymmetric Catalysis: The Power is in the Numbers
In the 1980s the need to synthesize many chemical compounds rapidly and inexpensively
spawned a new field in chemistry known as combinatorial chemistry. Based on the solid-phase
chemistry developed by Merrifieldviii, the possibility to prepare large quantities of compounds –
so called libraries – in a similar way on a solid support and screen them with a high-throughput
method arose. It is only recently that solution phase libraries have become favourable. The power
of this approach is in the numbers. The cycle of design, synthesis and testing is repeated many
7
times in contrast to the classical method of one molecule at the time (Figure 2)ix.
DESIGN
TEST
DESIGN
SYNTHESIZE
TEST
COMBINATORIAL
SYNTHESIZE
CLASSICAL
Figure 2. Classical versus Combinatorial Chemistry
By producing larger and more diverse libraries, companies increase the probability of finding new
compounds of significant therapeutic or commercial value. While the techniques of this growing
field finds his primary use in the discovery of candidate drugsx, combinatorial chemistry has
found his applications in various areas such as semi-conductors, polymers and catalysts.
1.5 Monodentate Ligand Combination Approach
The unique advantage of monodentate ligands is the possibility to use two different monodentate
ligands instead of one bidentate for the formation of a chiral catalyst. In the monodentate ligand
combination approach, one equivalent of each of two monodentate ligands is used to form two
homo-complexes and one hetero-complex (Scheme 4).
L1
L1
homo-complex 1 25%
M
L1
[M] + L1 + L2
L2
hetero-complex
M
L2
L2
50%
homo-complex 2 25%
M
Scheme 4. The formation of homo and hetero complexes in monodentate ligands combinations
When the hetero-complex shows higher activity and selectivity than both the homo-complexes in
the mixture it will lead to better results of the reaction as a whole. Something to keep in mind is
that these better results are obtained, only if the more selective hetero-complex is more active
than both the homo-complexes. This approach is not only useful for the combination of two chiral
ligands, hetero-complexes formed from a combination of a chiral and an achiral ligand or a ligand
with dynamic chirality could also lead to better results. This idea finds great benefit in the
combinatorial screening methods, because a small number of monodentate ligands can produce
large quantities of hetero-complexes. Mixtures of ligands have been used before in the formation
of chiral catalysts but until Reetz et al. came with the principle of mixtures of chiral monodentate
P ligandsxi, it was limited to bidentate ligands. Many examples for homo-complexes, which often
8
lead to high enantioselectivities are known in literature, but few is reported in about the use of
hetero-complexes.
1.6 Supramolecular Strategies in Combinatorial Asymmetric Catalysis
Over the past years, supramolecular chemistry has shown a phenomenal growth into major
scientific field. In traditional organic synthesis covalent bonds are made and broken to synthesize
the desired product. Supramolecular chemistry focuses on the non-covalent bonding interactions
of molecules, such as hydrogen bonds, Van der Waals forces, hydrophobic interactions and many
more. Important concepts in the field of host-guest chemistry, self-assembly and molecular
recognition have demonstrated its potential. The domain of supramolecular chemistry came of
age when D.J. Cram, J. Lehn and C.J. Pedersen were awarded the Nobel Prize in 1987 for their
work on host-guest assembliesxii. Little attention has been given to the application of
supramolecular strategies in transition metal catalysis.
V. Slagt reported a new strategy for the generation of chelating bidentate ligand by mixing two
monodentate ligands containing complementary binding sites. The assembly process was based
on selective metal-ligand interactions, using zinc(II) porphyrins and nitrogen donor ligandsxiii. B.
Breit and W. Seiche came with a concept for the in situ generation of bidentate donor ligands,
based on the self-assembly of a monodentate ligand in the coordination sphere of a metal center
through hydrogen bonding. 6-diphenylphosphanyl-2-pyridone provided a highly active and
regioselectivity catalyst for the selective hydroformylation of terminal alkenes (Scheme 5) xiv.
Ph2P
N
O
M
H
H
Ph2P
N
O
M
Ph2P
N
H
O
Ph2P
N
OH
6-DPPon
14
Scheme 5. Self-assembly of monodentate 6-DPPon through hydrogen bonding
Aiming towards technology for accelerated catalyst development and discovery, the University of
Amsterdam started the Cat-it Project in February 2005. In this project, hetero ligands are
selectively prepared in a synthesis robot using supramolecular strategies. The formation of heterocomplexes is possible through hydrogen bonding interactions. The synthesis of the hetero-ligand
is imposed by complementary binding motifs of mixed phosphite ligands. A library is made of the
9
series of ligands, and the catalyst is screened in 16 pressure reactors in a synthesis robot (Figure
3). The catalytic process is monitored using ultra fast-chiral gas chromatography.
Several homo- and hetero-ligand combinations were tested in rhodium catalyzed asymmetric
hydrogenation reactions. In the example given in Figure 3, ligand A acts as a donor ligand and is
combined with acceptor ligand B to form the hetero-complex AB. This hetero-complex shows
higher selectivity than both the homo-complexes in the asymmetric hydrogenation of dimethyl
itaconatexv.
O
A
P
O
95
O
ee (%)
N
100
O
H
O
B
N
O
84.8
85
85.4
80
O
75
O
70
P
88.1
90
Ph
AA
AB
BB
O
Figure 3. Hetero-complex AB proves potential in asymmetric catalysis / /synthesis robot
1.7 Project Goal
In this project the goal was set to synthesize (S)-2,2’-binaphtyl phosphite (Scheme 6, 15). Special
interest went to the formation of hydrogen-bonded complexes with this phosphite for rhodium
catalyzed asymmetric hydrogenation reactions.
H
O
O
O
P
15a
O
O
H
O
15b
M
P
OH
O
O
P
O
O
O
=
O
P
O
O
P
P
M
16
Figure 4. (S)-2,2’-binaphtyl phosphite as a monodentate for hydrogen bonded bidentate homo-complex
In Scheme 6, (S)-2,2’-binaphtyl phosphite is used to generate a hydrogen-bonded bidentate homocomplex. It is the aim to combine the phosphite with appropriate ligands, forming hetero-
10
O
complexes, which are hopefully more selective than their homo-combinations in rhodium
catalyzed asymmetric hydrogenation reactions.
2. Results and Discussion
2.1 Synthesis of (S)-2,2’-binaphtyl phosphite
The preparation of (S)-2,2’-binaphtyl phosphite (15) requires two steps and starts with the solvent
free reaction of (S)-1,1-2 binaphtol (17) with PCl3 under reflux in inert atmosphere and dry
environment, followed by the treatment of the resulting chlorophosphite (18) with one equivalent
of water in the presence of triethylamine (Scheme 7)xvi. Filtration and drying in vacuum resulted
in a white amorphous powder.
OH
PCl3
OH
reflux
O
O
17
1 eq. H2O
P
O
Cl
O
P
O
Et3N
15a
H
18
0.5 eq. H2O
O
O
P O P
O
O
Et3N
19
Scheme 7. Synthesis of (S)-2,2’-binaphtyl phosphite
The P31-NMR showed the desired hydrolyzed phosphite ( =14.59) and the pyrophosphite (19)
as a side-product ( =137.07). Pyrophosphites are known from literaturexvii and they are formed
when the chlorophosphite and (S)-2,2’-binaphtyl phosphite combine. More water was added and
the reaction was followed with NMR. The pyrophosphite was converted into the desired product,
and purification was done by recrystalization in dichloromethane and hexane. Recrystalization in
toluene and purification over a silica column using ethyl acetate or dichloromethane as eluens
decomposed the phosphite to (S)-1,1-2 binaphtol. The product was 95 % pure.
Compounds like (S)-2,2’-binaphtyl phosphite are not really suitable to coordinate sufficiently to
transition metals. Their potential arises through the tautomerism in which the pentavalent 15a is
in chemical equilibrium with the trivalent 15b, as depicted in Scheme 8.
O
O
P
15a
O
O
H
O
M
P
15b
OH
O
O
P
OH
M
11
Scheme 8. Tautomerization equilibrium and shift upon metal coordination
The equilibrium lays far to the left, which is seen in the H-NMR of (S)-2,2’-binaphtyl phosphite
(Spectrum 1). The hydrogen attached directly to the phosphor atom is split by the phosphor and
vice versa, resulting in doublet. Because phosphor gives large couplings, the peaks of the doublet
are far apart ( = 8.5 and 6.1 ppm).
Spectrum 1. H-NMR of (S)-2,2’-binaphtyl phosphite
J. Chatt and B.T. Heaton had pointed out that the equilibrium of pentavalent phosphine oxides
and trivalent phosphinous acids shifts to the right upon coordination to a suitable metal center xviii.
Knowing this, Roundhill and coworkers synthesized a hybrid platinum complex by reaction of the
platinum tetrakisphosphine complex with diphenylphosphine oxide (Scheme 9, A)xix. Something
interesting in the ligand coordination is the intramolecular hydrogen bond in the backbone that
leads to a quasi chelate giving extra conformational stability to the complex. This complex is
insoluble in most organic solvents. No structural or spectral information was reported.
Ph
Ph
Ph
Pt(PPh3)4
+
2
O
H
P
Ph
A
P
O
Pt
H
Ph3P
H
P
Ph
+
3 PPh3
O
Ph
12
Scheme 9. Synthesis of a Pt hybrid complex stabilized by intramolecular hydrogen bonding.
2.2. Metal-Complex NMR studies
2.2.1 Platinum Complexes: Pt(PPh3)4 as Metal Precursor
Based on the article of Roundhill and coworkers, complexes were synthesized with platinum
tetrakisphosphine and 2 equivalents of (S)-2,2’-binaphtyl phosphite. Complex A, which is drawn
below in Scheme 10, was expected to be seen. Three triphenyl groups would be replaced by two
phosphite ligands and one hydrogen atom coming from the oxidative insertion of one of the
phosphites. In Spectrum 2, P31-NMR is shown 30, 100 and 150 minutes after addition of solvent
(CLCl3).
H
O
O
Pt(PPh3)4
O
O
H
O
O
P
+ 2
A
O
O
P
P
Pt
+
O
3 PPh3
H
Ph3P
OH HO
O
O
O
B
O
P
P
Pt
P
P
O
O
O
O
OH
HO
Scheme 10. Complex formation of Pt(PPh3)4 with (S)-2,2’-binaphtyl phosphite
Table 1. Peak Assignment of Spectrum 2.
 (ppm)
Assignment
99.7
Complex B
30.2
Pt(PPh3)4
14.3
phosphite
3.8
P-acid
13
Spectrum 2. P31-NMR of the complex formed with Pt(PPh3)4 and 2 equiv. of (S)-2,2’-binaphtyl phosphite
If complex A would be formed, multiple peaks should be seen: The Pt-phosphine coupling, as
well as the Pt -phosphite and phosphine-phosphite coupling. It is clear from the P31-NMR that
the desired product was not formed. The peak assignment of Spectrum 2 is summarized in Table
1. The peaks at 30.3 and 14.3 ppm could be assigned to the metal precursor Pt(PPh 3)4 and free
phosphite ligand. A singlet arose at 99.7 ppm and it could possibly be assigned to complex B
depicted in Scheme 10. All of the triphenylphosphine could be replaced by phosphite ligand,
resulting in a complex with four similar phosphorus atoms, explaining the singlet in the spectrum.
2.2.2 Platinum Complexes: Pt(PPh3)2Cl2 as Metal Precursor
J.M. Solar and R.D. Rogers reported the synthesis of alkyl phosphite Pt(II) complexes and their
structural and spectral characterizationxx. In order to form [Pt(P(OH)(OMe)2)2(P(O)(Ome)2)2], a
solution of K2PtCl4 in H2O was added dropwise with continuous stirring to an aqueous mixture of
KOH and the appropriate amount of P(OMe3) at 75 ºC. The solution was cooled overnight in air
and a white crystalline material precipitated. The product was filtered and washed with a 50%
ethanol/water mixture. The structure of [Pt(P(OH)(OMe)2)2(P(O)(Ome)2)2] was determined by Xray diffraction (Figure 5).
The Pt atom resides on a crystallographic center of inversion
H
and is coordinated to four phosphor atoms in a square planar
geometry. The two P-ligands are linked via a symmetric
hydrogen bond as can be seen in Figure 5. The P31-NMR
showed a singlet at 90 ppm.
H
Figure 5. Molecular Structure of [Pt(P(OH)(OMe)2)2(P(O)(Ome)2)
Based on the article of Solar and Rogers, complexes were made with the Pt(II) precursor
Pt(PPh3)2Cl2. Two equivalents of phosphite were added to Pt(PPh3)2Cl2, hoping that complex C in
Scheme 11 would be formed.
Ph3P
Ph3P
PPh3
Pt
Cl
O
+ 2
Cl
O
P
O
H
O
PPh3
Pt
P
O
P
O
C
O
OH HO
Scheme 11. Complex formation of Pt(PPh3)2Cl2 with 2 equivalents of hydrolyzed phosphite
14
It was expected that the two chloride atoms would be replaced by the phosphite ligand, rather
than the triphenyl phosphine groups, based on a concept called the trans-effect. This concept was
introduced in the platinum chemistry by Chernyaev in 1926xxi. The trans effect is best defined as
the effect of a coordinated ligand upon the rate of substitution of ligands opposite to it. It is
attributed to electronic effects and it is most notable in square planar complexes, although it can
also be observed for octahedral complexes. Because the PPh3 is a very electronegative group, it
weakens the bond of the group that is trans to it, which makes the Cl more easily substituted
rather than the PPh3.
The P31-NMR is shown in Spectrum 3 and the peak assignment is summarized in Table 2.
Table 2. Peak assignments of Spectrum 3
 (ppm)
Assignment
72.2
Complex
27.9
Pt-PPh3
24.4
Pt-PPh3
15.1
Pt(PPh3)2Cl2
14.5
Phosphite
7.7
P-acid, side prod.
4.6
P-acid, side prod.
-4.2
PPh3
Spectrum 3. P31-NMR of Pt(PPh3)2Cl2 with 2 equivalents of (S)-2,2’-binaphtyl phosphite
The spectrum did not expose a lot and it is hard to tell which complex was formed. There was still
a lot of free metal precursor and phosphite ligand present in solution (  : 15.1 and 14.5 ppm). At
72.2 ppm a singlet ariso, indicating a highly symmetrical complex was formed. Two broad
singlets were seen at 27.9 and 24.4 ppm, which could be assigned to the Pt-P coupling from the
PPh3. It could also be there were other complexes present in solution, which could account for
these peaks. The peaks at 7.7 and 4.6 ppm are probably coming from phosphor-acids that were
formed during the reaction. The phosphite was not completely pure and this could be the reason
these side-products were formed. The peak at - 4.2 ppm is assigned to free PPh3. The desired
complex was not formed, because a doublet should be visible from the coupling of the PPh 3 with
the phosphor from the phosphite ligand.
15
The experiment was repeated, and based on the article of Solar, 1 equivalent of Et 3N was added.
The base would theoretically capture one proton, which would allow the formation of a hydrogen
bonded bidentate complex. P31-NMR was taken and the Spectrum 4 was obtained.
Table 3. Peak Assignment of Spectrum 4.
 (ppm)
Assignment
60.3
Complex
27.5
Pt-PPh3
24.6
Pt-PPh3
7.7
P-acid, side prod.
4.6
P-acid, side prod.
-4.7
PPh3
Spectrum 4. P31-NMR of Pt(PPh3)2Cl2 with 2 eq. of (S)-2,2’-binaphtyl phosphite and 1 eq. of Et3N
The spectrum looked quite similar to Spectrum 3, with the exception of a remarkable shift! The
peak at 72.2 ppm in Spectrum 3 shifted to 60.3 ppm and the peaks of the free metal precursor and
phosphite ligand were no longer visible. It is clear a highly symmetrical complex was formed,
but the exact structure could not be derived from these spectra only. Adding 1 equivalent of base
changed the spectrum and obviously changed the structure of the complex. Because of a greater
interest in rhodium complexes, no more NMR studies with platinum precursors were performed.
2.2.3 Rhodium complexes: Rh(nbd)2BF4 as metal precursor
Rhodium complexes were formed by adding 2 to 4.5 equivalents of hydrolyzed phosphite to
Rh(nbd)2BF4 (Scheme 13). P31-NMR was taken and the spectrum is given below (Spectrum 5).
16
Figure 6
Spectrum 5.P31 NMR of Rh(nbd)2BF4 and 2 equiv. of (S)-2,2’-binaphtyl phosphite
In Spectrum 5 one doublet at 174.3 and 175.2 ppm was seen, indicating two similar phosphor
atoms, split by the rhodium. Complex E depicted in Scheme 12 was most probably formed.
BF4O
Rh+
+ 2
P
O
OH
O
O
P
O
H
D
Rh
OH HO
O
P
O
O
P
Rh
E
O
Scheme 12. Possible complex formation of Rh(nbd)2BF4 with 2 equiv. of hydrolyzed phosphite
After an hour multiple peaks were seen in the region of 150 to 200 ppm. The complex was not
stable and after a few hours all the phosphor in the solution precipitated.
When 1 equivalent of triethylamine was added to the complex, the solution changed from turbid
orange to clear red (Figure 6, 7). P31-NMR was taken and the spectrum is given below (Spectrum
6).
Figure 7
Spectrum 6. P31 NMR of NMR of Rh(nbd)2BF4 , 2 eq. of (S)-2,2’-binaphtyl phosphite and 1 eq. of Et3N
17
The remarkable color change was accompanied by a remarkable shift of 48 ppm in the spectrum.
The doublet of 174-175 ppm shifted to a doublet at 125.6 and 127.0 ppm! This could be an
indication for the formation of a hydrogen bonded rhodium complex.
Most probably complex G was formed, because in complex F, the phosphor atoms are not similar
(Scheme 13). An interesting thing to keep in mind is that complex G caries a negative charge,
stabilizing the complex as a whole. It replaces the BF4 as the anion. The electronic properties are
drastically changed, which could account for the enormous down field shift that was seen.
H
O
O
BF4-
O
O
+
Rh+
2
P
O
P
O
O
P
Rh
+ 1 eq. Et3N
O
F
O
H
H
O
O
O
O
P
Rh
O
P
G
O
Scheme 13. Possible complex formation of Rh(nbd)2BF4 with 2 eq. of hydrolyzed phosphite and 1 eq. of Et3N
2.3 Rhodium Catalyzed Asymmetric Hydrogenation Reactions
2.3.1 Homo-complexes of (S)-2,2’-binaphtyl phosphite and the effect of base addition
(S)-2,2’-binaphtyl phosphite was used to generate homo-complexes in four asymmetric
hydrogenation reactions (Scheme 14). Because of the remarkable shift in the P31-NMR of the
rhodium complexes upon base addition, the effect of base was tested in catalysis using different
equivalents of Et3N.
A
rh(nbd)2BF4
L
CO2Me
MeO2C
B
H2
*
N
H
CO2Me
2-methyl-acetamido-acrylate
CO2Me
H
N
O
dimethyl itaconate
CO2Me
MeO2C
Ac
Ac
N
H
C
*
H
N
*
N-(3,4-dihydronaphthalen-2-yl)acetamide
O
O
O
D
O
*
(E)-methyl 2-methyl-3-phenylacrylate
O
18
Scheme 14. Asymmetric hydrogenation reactions of four different substrates
A. Asymmetric hydrogenation of dimethyl itaconate
The catalysis results are summarized in Table 4.
Table 4.Catalysis results: The effect of base addition
N
Eq. base Conversion (%) ee(%)
1
0.0
100.0
57.0
2
0.5
100.0
62.2
3
0.75
100.0
63.6
4
1.0
100.0
67.6
5
1.0
100.0
71.8
6
1.25
100.0
72.1
7
2.0
100.0
79.6
8
3.0
100.0
28.4
CH2Cl2, RT, 10 bar, Rh/L1/L2 = 1/1.1/1.1
75
ee (%)
65
55
45
35
25
0
0.5
1
1.5
2
2.5
3
equiv. base
Graphic 1
conc. Rh 1 mM, conc. subs. 10 mM, react. time 16 h
The results in Table 4 show a significant trend: Adding no base resulted in an enantioselectivity
of 57 %. The highest ee value was obtained when 2 equivalents of Et3N were added, improving
the enantioselectivity with 20% (Graphic 1)! It is rather strange that the best result was obtained
with 2 equivalents, because theoretically only 1 equivalent should be added to remove the proton
from the phosphite. When more than 2 equivalents of base were added, the enantioselectivity
decreased fast. It looks like 1 equivalent of base was added twice, but this is a result coming from
a previous experiment which was done under the exact same conditions, and it can be used as an
extra measuring point (same for the following experiments).
B. Asymmetric hydrogenation of 2-methyl-acetamido-acrylate
The catalysis results are summarized in Table 5.
Table 5. Catalysis results: The effect of base addition
Eq.
Conversion (%)
ee(%)
60
0.0
0.5
0.75
1.0
1.0
1.25
2.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
55.4
58.4
58.8
62.4
(20.1)
58.4
53.8
ee (%)
N
base
1
2
3
4
5
6
7
50
40
30
0
0.5
1
1.5
equiv.base
2
2.5
3
19
8
3.0
100.0
34.3
CH2Cl2, RT, 10 bar, Rh/L1/L2 = 1/1.1/1.1
conc. Rh 1 mM, conc. subs. 10 mM, react. time 16 h
Graphic 2.
The same trend was seen for 2-methyl-acetamido-acrylate, but it was less remarkable. Without
base, enantioselectivity of 55.4 % was obtained. An increase of 7 % ee was seen, going up to 62.4
% when 1 equivalent of Et3N was added (Graphic 2).
A strange result was obtained with N 5 in Table 5. The solution of this vial was grey and, whilst
all the others were orange. There was also not enough solvent added to the vial, so probably
something went wrong in the synthesis robot.
C. Asymmetric Hydrogenation of N-(3,4-dihydro-2-naphtalenyl)acetamide
The catalysis results are summarized in Table 6.
Table 6. Catalysis results: the effect of base addition
Eq. base Conversion (%) ee(%)
0.0
14.2
48.7
0.5
13.7
54.2
0.75
11.9
56.5
1.0
11.6
62.4
1.0
11.4
59.7
1.25
0.2
33.7
2.0
9.3
27.8
3.0
100.0
4.0
60
ee (%)
N
1
2
3
4
5
6
7
8
40
20
0
0
CH2Cl2, RT, 10 bar, Rh/L1/L2 = 1/1.1/1.1
conc. Rh 1 mM, conc. subs. 10 mM, react. time 16 h
0.5
1
1.5
2
2.5
3
equiv. base
Graphic 3.
For the N-(3,4-dihydro-2-naphtalenyl)acetamide lower conversion was obtained in all entries,
excepted for N 8. But the trend goes on! Without base, enantioselectivity of 48.7% was obtained.
Adding 1 equivalent of Et3N improved the ee with 12 %, up to a maximum of 62.4%.
D. Asymmetric Hydrogenation of (E)-methyl 2-methyl-3-phenylacrylate
In the fourth hydrogenation reaction, only 3 different equivalents of base were added. The
catalysis results are summarized in Table 7.
Table 7. Catalysis results: the effect of base addition
N
Base eq. Conversion (%) ee (%)
1
1.0
11.6
25.1
2
2.0
9.3
2.3
3
3.0
/
/
CH2Cl2, RT, 10 bar, Rh/L1/L2 = 1/1.1/1.1
conc. Rh 1 mM, conc. subs. 10 mM, react. time 16 h
.
20
The conversion and the enantioselectivities were a lot lower compared to the other reactions with
the other substrates. Maximal ee of 25.1 % was obtained upon addition of 1 eq. of Et3N.
21
2.3.2. Hetero-complexes of (S)-2,2’-binaphtyl phosphite
(S)-2,2’-binaphtyl phosphite was used to generate hetero-complexes in the asymmetric
hydrogenation of dimethyl itaconate and 2-acetamido-acrylate (Scheme 15, A & B). (S)-2,2’binaphtyl phosphite was combined with five ligands as depicted in Scheme 17. An example of a
hetero-complex is drawn on the right of this scheme. Ligand B was taken as a comparison for the
hydrolyzed phosphitexxii. Combinations were made with two acyl phosphites C and D that were
synthesized following the reaction given in Scheme 18
xxiii
. Ligands Exxiv and Fxxv were
synthesized by colleagues and ligand G was obtained from Sigma Aldrich.
ACCEPTOR LIGANDS
O
C
O
P
DONOR LIGANDS
O
A: (S)-2,2'-binaphtyl phosphite
B: as a comparison
P
A
P
O
CH3
H
OH
E
O
O
P
B
CH3
O
CH3
NH
O
O
N
O
P
O
O
O
P
O
A
O
D
O
O
O
O
P
F
O
P
C
O
O
O
N
O
C & D: acyl phosphites
E: Monophos
F: phtalimide phosphite
G: diphenyl-2-pyridylphosphine
O
G
Ph
N
P
Ph
Scheme 17. Donor and acceptor ligands used for the generation of hetero-combinations
O
P
O
Cl
RCOONa
THF
O
P
C (R = Me)
D (R = Ph)
O
O
O
R
Scheme 18. Synthesis of acylphosphites C and D from Figure 8
O
A. Asymmetric Hydrogenation of dimethyl itacontate
The catalysis results are summarized in Table 8.
Table 8. Rh-catalyzed hydrogenation of dimethyl itaconate
N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ligands
(S)-A / (S)-A
(S)-B / (S)-B
(S)-C / (S)-C
(S)-D / (S)-D
(R)-E / (R)-E
(S)-F / (S)-F
G/G
(S)-A / (S)-C
(S)-B / (S)-C
(S)-A / (S)-D
(S)-B / (S)-D
(S)-A / (R)-E
(S)-B / (R)-E
(S)-A / (S)-F
(S)-B / (S)-F
(S)-B / G
Conversion (%)
100.0
100.0
100.0
100.0
100.0
100.0
1.2
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
ee(%)
64.0
76.3
43.2
43.8
> 99.9
83.2
0.0
53.6
77.1
62.2
76.8
99.6
2.7
64.0
81.0
37.0
Config.
S
S
S
S
S
S
R
S
S
S
S
S
S
S
S
S
CH2Cl2, RT, 10 bar, Rh/L1/L2 = 1/1.1/1.1
conc. Rh 1 mM, conc. subs. 10 mM, react. time 16 h inc. time 2 h
It seemed that the hetero-complexes that were formed with (S)-2,2’-binaphtyl phosphite were not
more selective than their homo-combinations. Two ‘mini-hits’ were obtained with donor ligand
B: entry 9 and 11 showed an improvement of 0.8 and 0.5 % enantioselectivity (Figure 8, 9,
Graphic 4, 5).
100
B
O
80
N
76.3
77.1
ee (%)
P
O
H
60
Figure 8
O
43.2
C
O
P
40
O
BB
Graphic 4
O
BC
CC
.
100
B
O
P
N
O
80
Figure 9
O
P
O
76.8
60
D
O
76.3
ee (%)
H
O
CH3
43.8
Graphic 5
40
BB
BD
DD
23
B. Asymmetric Hydrogenation of 2-methyl-acetamido-acrylate
The catalysis results are summarized in Table 9.
Table 9. Rh-catalyzed hydrogenation of 2-methyl-acetamido acrylate
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ligands
(S)-A / (S)-A
(S)-B / (S)-B
(S)-C / (S)-C
(S)-D / (S)-D
(R)-E / (R)-E
(S)-F / (S)- F
G/G
(S)-A / (S)-C
(S)-B / (S)-C
(S)-A / (S)-D
(S)-B / (S)-D
(S)-A / (R)-E
(S)-B / (R)-E
(S)-A / (S)- F
(S)-B / (S)-F
(S)-B / G
Conversion (%)
100.0
100.0
100.0
100.0
100.0
100.0
83.3
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
ee(%)
51.9
64.3
74.0
86.2
97.1
79.2
0.0
67.3
75.1
66.9
72.3
87.3
15.7
79.9
80.1
57.5
Config.
S
S
S
S
R
S
S
S
S
S
S
R
R
S
S
S
CH2Cl2, RT, 10 bar, Rh/L1/L2 = 1/1.1/1.1
conc. Rh 1 mM, conc. subs. 10 mM, react. time 16 h, inc. time 2 h
Hetero-combinations formed with (S)-2,2’-binaphtyl phosphite showed higher selectivity when
combining with the phtalimide phosphite F (Entry 14), an increase of 0.7 % ee was measured
(Figure 10, Graphic 6). Donor ligand B gave a mini-hit with ligand F (Entry 15) and C (Entry 9)
improving the ee with 0.9 % and 1.1 % respectively. (Figure 11, 12 and Graphic 7,8)
A
O
P
100
O
O
H
ee (%)
Figure 10
80
O
F
O
P
60
O
79.9
.9
79.2
AF
FF
51.9
N
O
.
Graphic 6
40
O
AA
100
B
O
P
N
O
H
Figure 11
O
ee (%)
80
75.1
74.0
BC
CC
64.3
60
C
O
P
O
O
Graphic 7
40
BB
24
B
O
P
100
N
O
H
ee (%)
Figure 12
80
O
P
79.2
BF
FF
64.3
60
F
O
80.1
O
N
O
Graphic 8
O
40
BB
3. Conclusions and Future Work
(S)-2,2’-binaphtyl phosphite was synthesized and from the metal-complex NMR studies can be
concluded that the addition of base changes the structures of complexes formed with Pt(PPh3)2Cl2
and Rh(nbd)2BF4. By adding the appropriate amount of Et3N complexes stabilized through
hydrogen bonding interactions might be formed. It is hard to tell what the structures of the
complexes were based on P31 NMR only. Obtaining crystals is therefore a must to gain more
insight in the behavior and formation of these complexes, and it is high upon the list of future
work.
When (S)-2,2’-binaphtyl phosphite was used to generate homo-combinations, it was seen that
base addition greatly improved the enantioselectivity in the asymmetric hydrogenation reaction of
dimethyl-itaconate. Adding 2 equivalents of Et3N increased the ee from 57 % to 79.6 %! The
same trend, though less significant, was seen for the hydrogenation of 2-methyl-acetamido
acrylate and N-(3,4-dihydro-2-naphtalenyl)acetamide, upon the addition of 1 equivalent of base.
So, adding the proper amount of base improves the enantioselectivity, and excess base
deteriorates the enantioselectivity. These hydrogen bonded bidentate complexes have great
potential as a new class of ligands for asymmetric hydrogenation reactions. Repeating these
reactions with other BINOL-based hydrolyzed phosphites, substrates, bases and base equivalents
is definitely something that deserves special attention in the future.
No remarkable results were obtained when (S)-2,2’-binaphtyl phosphite was used to generate
hetero-complexes. There were some mini-hits, but no more than 1.1 % improvement in ee was
achieved. The length of the acceptor group to the metal center differs in the ligands that were
used. It is important to find out more on the influence of the backbone of the hetero-complexes,
as they could affect the enantioselectivities. Metal-complex NMR-studies with the heterocomplexes that were formed might give more insight in the behavior and formation of the
catalysts.
25
4. Experimental Section
Equipment
Routine 1H and 31P{1H} NMR spectra were recorded on a Varian Mercury 300 MHz (300.1 MHz
for 1H, 121.5 MHz for 31P{1H}). Complex NMR studies were done on a Varian Inova 500 MHz
(499.8 MHz for 1H, 202.3 MHz for 31P{1H}).
Asymmetric Hydrogenation reactions were performed in a Chemspeed accelerator TM SLT100
Synthesizer. For the determination of the enantiomeric purities for the hydrogenation of dimethyl
itaconate an Interscience HRGC (equipped with a Supelco β-dex column) was used.
Determination of the enantiomeric purity for the hydrogenation of 2-methyl-acetamido acrylate,
Interscience Trace GC Ultra equipped with an ultra fast chiral column (Ph MDEX column) was
used. The enantiomeric excess of N-(3,4-dihydro-2-naphtalenyl)acetamide and E-methyl 2methyl 3-phenylacrylate was obtained with an Interscience FOCUS GC equipped with a Varian
Capillary Column (CP-Chirasil-Dex CB).
Ligand Syntheses
All the ligands that were used in this project were synthesized following reaction routes described
in literature (references were given in the results section).
(S)-2,2’-binaphtyl phosphite was purified by recrystalization in dichloromethane and hexane.
General procedure of phosphite metal complexes for NMR studies
To a mixture of metal precursor Pt(PPh3)4 / Pt(PPh3)2Cl2 / Rh(nbd)2BF4 in CDCl3 2 to 4
equivalents of (S)-2,2’-binaphtyl phosphite were added. One equivalent of Et3N was added to this
mixture 15 minutes after the solvent was added. 31P NMR was taken.
- Rh(nbd)2BF4 (5.63 mg, 0.015 mmol) and 2 equiv. of (S)-2,2’-binaphtyl phosphite (9.96 mg,
0.029 mmol) were added in 1 ml of CDCl3. 31P NMR (121.5 MHz, CDCl3, 25ºC): δ = 174.8 (d,
JRh-P = 450 Hz) [complex E].
- Rh(nbd)2BF4 (5.63 mg, 0.015 mmol) and 2 equiv. of (S)-2,2’-binaphtyl phosphite (9.96 mg,
0.029 mmol) were added in 1 ml of CDCl3. One equivalent of Et3N (2.08 l, 0.015 mmol) was
added. 31P NMR (121.5 MHz, CDCl3, 25ºC): δ = 126.3 (d, JRh-P = 700 MHz) [Complex G].
26
General procedure for the asymmetric hydrogenation reactions
Reactions were performed in a Chemspeed acceleratorTM SLT100 Synthesizer. The metal
concentration was 0.5 mM, the ligand/metal ratio was 2.2 and the metal/substrate ratio 0.01. To
the reactor, 0.5 ml of metal, 1 ml of substrate and 0.5 ml of ligand 1=ligand 2 were added. The
reaction time was 16 hours and the reactions were done at room temperature under pressure of 10
bar. Dry dichloromethane was used as solvent. In the asymmetric hydrogenation reactions with
the hetero-complexes there was a 2-hour incubation time. For the reactions with the homocomplexes seven different equivalents of base (0, 0.5, 0.75, 1, 1.25, 2, 3) were added and there
was no incubation time.
5. Refrences
i
J.A. Osborn, F.H. Jardine, J.F. Young, G. Wilkinson, J. Am. Chem. Soc 1966, 1711
ii
Knowles, W. S.; Sabacky, M. J. Chem. Commun. 1968, 1445.
iii
Dang, T. P.; Kagan, H. B. J. Chem. Soc. D: Chem. Commun. 1971, 481.
iv
Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518.
v
Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R,
J. Am Chem. Soc. 1980, 102, 7932.
vi
van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries, A. H., M.;
de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539.
vii
Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889.
viii
Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
ix
A. Duursma, Proefschrift, Asymmetric catalysis with chiral monodentate
phosphoramidite ligands, RU Groningen, 2004, pg. 19
x
Coffen, D. L.; Luithle, J. E. A. Handbook of Combinatorial Chemistry, Eds
Nicolaou, K. C.; Hanko, R.; Hartwig, W., Wiley-VCH, Weinheim, 2002, p 10.
xi
Reetz et al. Angew.Chem. Int. Ed. 2003, 42, No. 7, 790 – 793
xii
Donald J. Cram, Science, 1983, 219, 1177-1183
C. J. Pedersen, J. Am. Chem. Soc.1967, 89, 7017.
xiii
V.F. Slagt, P.C.J. Kamer, P.W.N.M. van Leeuwen, J.N.H. Reek,
J. Am. Chem. Soc. 2004, 126, 1526-1536
xiv
B. Breit, W. Seiche, J.Am.Chem.Soc. 2003, 125, 6608-6609
27
xv
B. Sandee, J. Meeuwissen, L. van den Burg, Poster Cat-it
xvi
X. Linghu, J.P. Potnick, J.S. Johnson, J. Am. Chem .Soc., 2004, 126, 3070-3071
xvii
A. Korostrylev et al./ Tetrahedron: Asymmetry 14 (2003) 1905 – 1909
xviii
J.Chatt, B.T. Heaton, J.Chem.Soc.A 1968, 2745 – 2757
xix
W.B. Beaulieu, T.B. Rauchfuss, D.M. Roundhill, Inorg. Chem. 1975, 14, 1732-1734
xx
J.M. Solar, R.D. Rogers, W.R. Mason, Inorg. Chem, 1984, 23, 373-377
xxi
Chernyaev, I.I Ann. Ins. Platine (USSR) 1926, 4, 243-275
xxii
Lefort L., Boogers J.A.F., de Vries A.H.M., de Vries J. G., Org. Lett., 2004,Vol 6, No 11,
xxiii
A. Korostylev et al. / Tetrahedron: Asymmetry 15 (2004) 1001-1005
xxiv
xxv
R. Hulst, N.K. De Vries, B.L. Feringa / Tetrahedron: Asymmetry 1994, 5; 699
J. Meeuwissen, unpublished results
28