Tunable furanoside diphosphite ligands. A powerful approach in asymmetric catalysis

Article abstract of DOI:10.1039/b303303a

A series of highly tunable furanoside diphosphite ligands, derived from readily available D-(+)-xylose and D-(+)glucose, are discussed. Their modular nature allows a facile systematic variation in the configuration of the stereo-centres at the ligand bridge and in the biaryl substituents. This enabled to select a ligand for each particular reaction that provided enantioselectivities that are comparable to those of the best catalysts previously reported in different asymmetric reactions. The Royal Society of Chemistry 2003.

Full text of DOI:10.1039/b303303a

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Tunable furanoside diphosphite ligands.
A powerful approach in asymmetric catalysis
Montserrat Diéguez, Aurora Ruiz and Carmen Claver*
Departament de Química Física i Inorgànica, Universitat Rovira i Virgili,
Pl. Imperial Tàrraco 1, 43005 Tarragona, Spain
Received 24th March 2003, Accepted 9th May 2003
First published as an Advance Article on the web 28th May 2003
A series of highly tunable furanoside diphosphite ligands,
derived from readily available D-(؉)-xylose and D-(؉)-
glucose, are discussed. Their modular nature allows a facile
systematic variation in the configuration of the stereo-
centres at the ligand bridge and in the biaryl substituents.
This enabled to select a ligand for each particular reaction
that provided enantioselectivities that are comparable to
those of the best catalysts previously reported in different
asymmetric reactions.
of new ligands for efficient asymmetric catalysis is still mainly
empirical (based on trial-and-error).
For many years a large number of chiral ligands, mainly
P- and N-containing ligands with either C2- or C1-symmetry,
have been successfully applied in asymmetric catalysis.1
Diphosphines have played a dominant role among the
P-ligands, but recently a group of less electron-rich phosphorus
compounds – phosphite ligands – has received much attention.
Phosphite ligands have been successfully applied in many tran-
sition-metal-catalysed reactions such as hydrogenation, hydro-
formylation, hydrocyanation and allylic alkylation.2 These
ligands are extremely attractive for catalysis because they are
easy to prepare from readily available starting materials and are
also less sensitive to air than phosphines.3 However, a system-
atic evaluation of the effectiveness of these phosphite ligands is
hampered by the lack of systematically designed series of them
having a similar backbone.4 Such a task becomes significantly
more facile if readily modulable chiral ligands are at hand.
Carbohydrate-based ligands are particularly useful for address-
ing this need.2f–i,k,5 They are readily available and highly func-
tionalised with several stereogenic centres. This allows the
systematic regio- and stereoselective introduction of different
functionalities. Series of chiral ligands can be synthesised and
screened in the search for high activities and selectivities for
Introduction
Asymmetric reactions catalysed by transition metals are one of
the most efficient methods for preparing a wide range of enan-
tiomerically pure compounds.1 To achieve the highest levels of
reactivity and selectivity in catalytic enantioselective reactions,
different reaction parameters must be explored and adjusted. In
this optimization process, a careful selection and design of the
chiral ligand is perhaps the most crucial step since the best
ligand strongly depends on each particular reaction. Although
much progress has been made in this area in the last few years,
as is demonstrated by the large amount of relevant literature,1
there is no straightforward way of predicting, a priori, which
ligand will provide the highest selectivity. Therefore, the design
Montserrat Diéguez studied chemistry at Aurora Ruiz was born in Berlanga de Carmen Claver is Professor of Inorganic
the Rovira i Virgili University in Tarragona Duero, Soria, Spain, in 1954. She studied Chemistry at the University Rovira i Virgili
(Spain), where she received her Ph.D. in Chemistry at the Universitat de Barcelona in Tarragona (Spain), a position she has
1997 working in the group of Prof. C. (UB) and received her PhD at the same held since 1991. She received her Ph.D. in
Claver. After a year as a postdoctoral University in 1983. She is professor of 1978 from the University of Zaragoza
fellow with Prof. R.H. Crabtree at Yale Inorganic Chemistry at the Faculty of (Spain) working in the field of
University, in New Haven (USA), she Chemistry of Univesitat Rovira i Virgili organometallic chemistry with Prof. Luis
returned to Tarragona in 1999. She is (URV) in Tarragona. Her current research A. Oro. Her research is focused on
currently working as associated professor field is homogeneous catalysis covering fundamental aspects of homogeneous
at the Rovira i Virgili University. Her aspects of synthesis, characterisation of catalysis with transition metals, especially
present
research
is
focused
on chiral organometallic complexes and their in
asymmetric
catalysis
and
organometallic chemistry, mainly the application in asymmetric catalysis polymerization processes.
synthesis of chiral ligands and asymmetric including hydrogenation and carbon–
catalysis.
carbon bond formation processes.
Montserrat Diéguez
Aurora Ruiz
Carmen Claver
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
D a l t o n T r a n s . , 2 0 0 3 , 2 9 5 7 – 2 9 6 3
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each type of reaction. This tuning of the ligand structure
allows a rational design of ligands which also provides valuable
information about the origin of the selectivity. In this way, we
are not simply subject to the winds of chance when designing
new generations of catalysts.
In this context, in the last few years, we have developed a new
class of highly modular 1,2-protected diphosphite ligands with
furanoside backbones (Fig. 1) that promote a wide range of
catalytic asymmetric reactions.2f–h,k,6
ligands 1 and 2 whose configuration of C-3 is opposite. Ligands
3–6 provided an insight into the effect of a new stereocentre
at the carbon atom C-5. These ligands include the four
diastereomers that can be obtained by varying the configur-
ation of C-3 and C-5. We used them to systematically study
what effects these configurations have and whether there are
any cooperative effects between them.
We also studied how attaching different groups to the ortho-
and para-positions of the biphenyl moieties affects enantio-
selectivity with ligands 1–6(a–d). Finally, we used the series of
enantiomerically pure binaphthol-based ligands 1–6(e–h) to
determine whether there is a cooperative effect between the
stereocenters of the ligand backbone and the configuration of
the biaryl phosphite moieties
Synthesis of diphosphite ligands
Diphosphite ligands 1–6 were synthesized very efficiently in one
step from the corresponding diols, which were easily prepared
on a large scale from -(ϩ)-xylose and -(ϩ)-glucose (Scheme
1). Therefore, reacting the corresponding diol with 2 equiv. of
the desired in situ formed phosphorochloridites in the presence
of base afforded ligands 1–6 as white air-stable solids.
Scheme 1 Synthesis of ligands 1–6: (a) refs. 7 and 8, (b) ref. 2f, (c) refs.
2f,k and 6c.
Asymmetric hydroformylation
The rhodium-catalysed asymmetric hydroformylation of
alkenes has attracted much attention as a potential tool for
preparing enantiomerically pure aldehydes under mild and
clean reaction conditions. Chiral aldehydes are important
precursors for synthesising biologically active compounds,
biodegradable polymers and liquid crystals.9
In the last ten years, several studies have reported a
remarkable improvement in the rhodium-catalysed asymmetric
hydroformylation based on the use of diphosphite2a,b or phos-
phine–phosphite2c,d (Binaphos) ligands. At this time, Binaphos
is the only ligand with a wide scope in this reaction.
In this section, we show how the modularity of diphosphite
ligands 1–6 was exploited to improve the regio- and enantio-
selectivity of the rhodium-catalysed hydroformylation of
styrene, which is usually used as a model substrate (Scheme 2).10
Initial experiments with ligands 1a–c provided low-to-good
regio- and enantioselectivities (Table 1, entries 1–3).8
Scheme 2 Hydroformylation of styrene with compounds 1–6.
Fig. 1 Furanoside diphosphite ligands 1–6.
Ligands 1b and 1c, which have sterically demanding groups
at the ortho positions of the biphenyl moieties, resulted in
higher regio- and enantioselectivities than the less sterically
encumbered unsusbtituted ligand 1a. Ligands 2, whose con-
figuration of carbon atom C-3 is opposite to that of ligands 1,
followed the same trend (Table 1, entries 4 and 5) but the sense
of the enantioselectivity was reversed.
Since ligands 1 and 2 have a phosphorus moiety bound to the
non-stereogenic centre C-5, we examined whether introducing a
new stereocentre at the C-5 position would improve the enantio-
selectivity. We therefore tested diphosphite ligands 3–6.2f,6c,11
In this paper, we report the opportunities these ligands pro-
vide for improving the performance of three types of asym-
metric catalytic reactions: hydroformylation, hydrogenation
and allylic alkylation.
The modular construction of these ligands allows sufficient
flexibility to fine-tune (a) the different configurations of the
carbohydrate backbone and (b) the steric and electronic proper-
ties of the diphosphite substituents in order to improve the
selectivity of these reactions. In this way, we studied the effect
of the stereogenic carbon atom C-3 on the sugar backbone with
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Table
1
Asymmetric hydroformylation of styrene catalysed by
Table
2
Asymmetric hydroformylation of styrene catalysed by
[Rh(acac)(CO)2] / diphosphite 1 and 2.a
[Rh(acac)(CO)2]/diphosphite 3b–f and 4b–h.a
Entry
Ligand
TOFb
% Conv.c
% 2-PPd
% eee
Entry
Ligand
TOFb
% Convc
% 2-PPd
% eee
1
2
3
4
5
1a
1b
1c
2b
2c
40
50
53
41
55
17
20
20
19
23
84
95
95
96
98
4 (S)
51 (S)
39 (S)
53 (R)
45 (R)
1
2
3
4
5
6
7
8
9
3b
4b
3c
4c
3d
4d
3e
4e
3f
131
98
64
49
81
66
73
72
77
78
83
82
73
52
99
97.8
96
97.3
95
96
84
85
86
85
49 (R)
78 (S)
36 (R)
62 (S)
30 (R)
76 (S)
5 (S)
25 (S)
20 (R)
60 (R)
68 (S)
30 (S)
165
134
147
151
158
153
178
165
149
99
a Reaction conditions: T = 40 ЊC, P = 25 bar, styrene (13 mmol),
[Rh(acac)(CO)2] (0.0135 mmol), ligand/Rh = 1.1, toluene (15 mL), PCO
/
PH = 1. b TOF in mol styrene × mol RhϪ1 × hϪ1 determined after 1 h
2
reaction time by GC. c % Conversion measured by GC after 5 h. d Regio-
selectivity for 2-phenylpropanal. e % Enantiomeric excess measured by
GC using a FS-Cyclodex β-I/P column.
10
11
12
4f
4g
4h
84
86
a Reaction conditions: T = 40 ЊC, P = 10 bar, styrene (13 mmol),
[Rh(acac)(CO)2] (0.0135 mmol), ligand/Rh = 1.1, toluene (15 mL), PCO
/
In a first set of experiments, ligands 3–6(b,c) were used to
investigate how the configurations of the stereogenic carbon
atoms C-3 and C-5 affect the selectivity. We expected their con-
figurations to be important because they are close to the metal.
These ligands constitute the four diastereomers that can be
obtained by varying the configuration of the C-3 and C-5 atoms
in the backbone in combination with two different bulky 2,2Ј-
biphenyl moieties. The selectivity results with these ligands can
be summarised as follows (Fig. 2):
PH = 0.5. b TOF in mol styrene × mol RhϪ1 × hϪ1 determined after 1 h
2
reaction time by GC. c % Conversion measured by GC after 5 h. d Regi-
oselectivity for 2-phenylpropanal. e % Enantiomeric excess measured by
GC using a FS-Cyclodex β-I/P column.
3b and 4b, suggested that bulky substituents in the para posi-
tions had a negative effect on enantioselectivity.
To further investigate how enantioselectivity was influenced
by the groups attached to the biaryl moieties, ligands e–h con-
taining different enantiomerically pure binapthyl moieties were
also tested (Table 2. Note that in this case these experiments
were carried out at 40 ЊC; For comparative purposes we also
include the results using ligands 3, 4(b–d) at 40 ЊC). In this case,
ligands 3 and 4 were chosen since they include two different
combinations of the stereocentres C-3 and C-5. Ligands 4
have the combination of configurations on C-3 and C-5
required to induce the highest enantioselectivity, while ligands 3
have an inappropriate configuration of carbon atoms C-3 and
C5 (vide supra).
Low enantioselectivity was found with ligand 4e, which has
an unsubstitituted (S)-binaphthyl moiety (Table 2, entry 8).
Changing the configuration of the binaphthyl moieties from (S)
to (R) (ligand 4f ) increased activity and enantioselectivity
(entry 8 vs 10). Moreover, the sense of the enantioselectivity
was reversed; the (S) enantiomer was obtained with 4e and the
(R) enantiomer was obtained with 4f. Ligands 3e and 3f, whose
configuration of carbon atom C-3 is opposite to those of lig-
ands 4, followed the same trend as catalyst precursors Rh/4e
and Rh/4f (entries 7 and 9). However, the enantiomeric excesses
were smaller because of the inappropriate configuration of
carbon atoms C-3 and C-5. If we compare these four results, we
find a cooperative effect between the stereogenic centres of the
ligand backbone and the stereogenic binaphthyl phosphite
moieties. This cooperative effect, together with the previously
observed cooperative effect between the backbone stereocentres
C-3 and C-5 controls enantioselectivity. From this, we can
also conclude that the excellent enantioselectivity found with
ligands 4b,d and 5b,d (vide supra) was due to the preferential
formation of the complex [HRh(L–L)(CO)2] (L–L = 1–6) with
the required conformation for optimal chiral cooperativity that
induces the highest enantioselectivity (see the section on the
characterisation of [HRh(L–L)(CO)2] complexes). We also
found that the sense of the enantioselectivity was controlled
by the configuration of the biaryl phosphite moieties. This
suggests that the configuration of fluxional biphenyl moieties
in ligands 3–6(b–d) is controlled by the configuration of the
stereogenic centre C-3.
Fig. 2 Visual representations of: (a) enantioselectivities and (b)
regioselectivities obtained with catalysts containing ligands 3–6(b,c), at
selected reaction conditions (P = 10 bar, T = 20 ЊC).
(a) The sense of the enantiodiscrimination was predomin-
antly controlled by the configuration at C-3. Accordingly,
ligands 4 and 6, with S configuration at C-3, gave (S)-2-phenyl-
propanal, while ligands 3 and 5, with R configuration at C-3,
gave (R)-2-phenylpropanal.
(b) A cooperative effect was observed between stereocentres
C-3 and C-5. That is, when the configuration of C-3 was S,
changing C-5 from R (ligand 4b) to S (ligand 6b) resulted in a
decrease in enantioselectivity from 90% S to 64% S. However,
when the configuration of C-3 was R; changing C-5 from R
(ligand 3b) to S (ligand 5b) increased the enantioselectivity
from 58% R to 89% R. This behaviour was also observed for
ligands 3–6(c).
From (a) and (b), we can see that either (S)- or (R)-2-phenyl-
propanal enantiomers can be obtained with excellent regio- and
enantioselectivities, under very mild reaction conditions, by
suitably selecting the diastereoisomeric ligands 4 or 5, respect-
ively. These results are among the best that have been reported
for the asymmetric hydroformylation of vinyl arenes.2a–c
We also found that the substituents in the para positions of
the biphenyl moieties effected the enantioselectivity, but regio-
selectivities were hardly affected (Fig. 2). Ligands 3–6(b) with
methoxy substituents always produced better enantioselec-
tivities than those with the corresponding tert-butyl-substituted
analogs (ligands 3–6(c)). To check whether this behaviour could
be attributed to steric problems with the tert-butyl groups in
para, we synthesised two new ligands 3d and 4d without these
groups, but still containing bulky substituents (trimethylsilyl
groups) in the ortho positions of the biphenyl moieties. The
results,12 which were similar to those we obtained with ligands
Finally, as expected, ligand 4g, which resulted from intro-
ducing bulky trimethylsilyl substituents at the ortho position of
the (S)-binaphthyl moieties in ligand 4e, improved enantio-
selectivity (68% ee, entry 11). Surprisingly, ligand 4h, with
bulky trimethylsilyl substituents at the ortho position of the
(R)-binaphthyl moieties, showed lower activity and lower
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Table 3 Calculated ee : ea ratio for [HRh(L–L)(CO)2] and selected
data for enantioselectivity
relationship is not always straightforward and several factors
must be considered:
(i) High bis-equatorially coordination preference does not
always lead to high selectivity because the enantiodiscrimin-
ation depends strongly on the exact ligand structure (vide supra).
Thus, ligand 4h which shows high bis-equatorially coordination
preference (ee : ea ratio of 98 : 2) shows very low enantio-
selectivity (Table 3).
(ii) A mixture of bis-equatorial and equatorial–axial species
does not always lead to low enantioselectivity, since the product
formation can be kinetically controlled. Thus, if one of the
diastereoisomeric species inserts the styrene into the Rh–H
bond faster than the other species, a good selectivity can be
obtained.14 The results using ligand 4f clearly show that enantio-
selectivity was good (Table 3) even with a 75 : 25 mixture of
ee : ea species.
Ligand
Ratio of ee : eaa
% ee at 40 ЊC
% ee at 20 ЊC
3b
3c
3d
4b
4c
4d
4f
4g
4h
5b
5c
6b
6c
85 : 15
90 : 10
98 : 2
100 : 0
100 : 0
99 : 1
75 : 25
100 : 0
98 : 2
100 : 0
99 : 1
49 (R)
36 (R)
30 (R)
78 (S)
62 (S)
76 (S)
60 (R)
68 (S)
30 (S)
77 (R)
59 (R)
48 (S)
31 (S)
58 (R)
46 (R)
52 (R)
90 (S)
74 (S)
90 (S)
–
81 (S)
–
89 (R)
76 (R)
64 (S)
52 (S)
88 : 12
89 : 11
a Measured from HP-NMR data.13
Asymmetric hydrogenation
asymmetric induction than the less hindered ligand 4f (entry 10
vs. 12). This unexpected low enantioselectivity can be explained
by considering that the bulky ligand probably reduces its steric
congestion in the hydridorhodium complex by adopting a non-
favourable conformation that reaches lower enantioselectivities.
The asymmetric hydrogenation of prochiral compounds
catalysed by chiral transition-metal complexes has been widely
used in stereoselective organic synthesis and some processes
have found industrial applications.1b–d For many years, the
scope of this reaction has been gradually extended in both
reactant structure and catalyst efficiency. Many chiral diphos-
phines1 and diphosphinites5a,d have been successfully applied
to metal-catalysed asymmetric hydrogenation. Recently, a
group of less electron-rich phosphorus compounds – phosphite
ligands – has received more attention. However, only Reetz
et al. have reported a successful enantioselective hydrogenation
using phosphite ligands.2i,j
In this section, we describe the results for the hydrogenation
of dimethyl itaconate with diphosphite ligands 1–6 (Scheme
3).2k,15 This substrate has been studied with a wide variety of
ligands carrying different donor groups. We can therefore
directly compare the efficacy of different ligand systems.
Characterisation of [HRh(L–L)(CO)2] complexes
To obtain information about species [HRh(L–L)(CO)2], which
are known to be the resting state in the hydroformylation reac-
tion,9 we studied the solution structures of hydridorhodium
diphosphite dicarbonyl catalysts [HRh(L–L)(CO)2] (L–L =
1–6), under syngas pressure by high-pressure NMR (HP-
NMR) and in situ high-pressure IR (HP-IR) spectroscopy.
These complexes are generally assumed to have a trigonal bi-
pyramidal structure and two isomeric structures of these com-
plexes are possible, containing the diphosphite coordinated in a
bis-equatorial (ee) or an equatorial–apical (ea) fashion (Fig. 3).
The studies reported below showed that the configurations of
the stereogenic carbon atoms C-3 and C-5 and the configur-
ation of the binaphthyl moieties greatly influenced the structure
of [HRh(L–L)(CO)2] and, therefore, the enantioselectivity.2f,6c
Scheme 3 Rh-Catalysed hydrogenation of dimethyl itaconate using
diphosphite ligands 1–6.
Initial experiments with ligands 1 and 2 provided low (22%
(R)) to moderate (64% (R)) enantioselectivities.2k In continued
efforts to improve the selectivity, we screened ligands 3–6,
related to 1 and 2, but with a new stereogenic centre at C-5
(Table 4). In this set of ligands, enantioselectivities were best
with ligands 3 with R configuration on both C-3 and C-5 stereo-
centres (Fig. 4). Moreover, the enantiomeric excesses depended
strongly on the absolute configuration of C-3 of the carbo-
hydrate backbone. This behaviour contrasted with the highly
Fig.
3
Equatorial–equatorial (ee) and equatorial–axial (ea)
coordination of diphosphite ligands in the [HRh(L–L)(CO)2]
complexes (L–L = 1–6).
The NMR data for complexes containing ligands 4b–d, 4g
and 5b,c indicate the formation of trigonal bipyramidal
(TBPY) hydridorhodium dicarbonyl species with equatorial–
equatorial (ee) coordinating diphosphites (Fig. 3). Further evi-
dence is provided by IR in situ measurements. Each spectrum
showed two carbonyl vibrations around 2070 and 2010 cmϪ1
,
which are characteristic of ee isomers.9d Moreover, the form-
ation of only one diastereoisomer was confirmed by variable-
temperature NMR.
For complexes containing ligands 3b–d, 4f, 4h and 6b,c,
NMR and IR spectra indicated an equilibrium between
equatorial–equatorial (ee) and equatorial–axial (ea) species
(Table 3).
If we compare the solution structures of the [HRh(L–L)-
(CO)2] species with results of hydroformylation (Table 3), we
can conclude that the enantiodiscriminating performance
is generally highest for ligands with strong bis-equatorial
coordination preference. However, this structure/selectivity
Fig. 4 A visual representation of the enantioselectivities obtained
with catalysts containing ligands 3–6(b,c).
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Table 4 Rh-Catalysed asymmetric hydrogenation of dimethyl itacon-
ate using diphosphite ligands 3–6.a
Table 5 Pd-catalysed asymmetric allylic alkylation using ligands 1–5.a
Entry
Ligand
t/h
% Convb
% eec
Entry
Ligand
% Convb (t/h)
% eec
1
2
3
4
5
6
7
8
9
1a
1c
2b
2c
3a
3b
3c
4a
4b
4c
5c
22
95
83
11
100
50
100
100
60
20 (S)
90 (S)
5 (R)
1 (R)
2 (R)
45 (R)
64 (R)
9 (S)
95 (S)
84 (S)
52 (S)
1
2
3
4
5
6
7
8
9
3b
3c
3d
3e
3f
4b
4c
4d
5b
5c
6b
6c
82 (8)
90 (8)
100 (6)
50 (8)
46 (8)
98 (8)
100 (8)
100 (8)
80 (8)
87 (8)
69 (8)
73 (8)
85 (R)
90 (R)
97 (R)
50 (S)
52 (R)
2 (R)
2 (R)
3 (R)
63 (R)
67 (R)
27 (R)
29 (R)
1.5
22
1.5
24
0.32
0.25
0.58
0.17
0.08
100
100
100
10
11
10
11
12
60
a All reactions were run at room temperature. Diphenylallyl acetate/
palladium = 100. Malonate/palladium = 300. Ligand/palladium = 1.
Catalyst preparation time is 30 min b Conversion determined by GC.
c Enantiomeric excesses determined by HPLC on a Chiralcel-OD
column.
a Reaction conditions: [Rh(cod)2]BF4 (0.01 mmol), Ligand/Rh = 1.1,
Substrate/Rh = 100, CH2Cl2 (6 mL), T = 25 ЊC, P = 5 bar. b % Conver-
sion measured by GC. c % Enantiomeric excess measured by GC using a
Chiraldex G-TA column.
cooperative effect between stereocenters C-3 and C-5 in Rh-
catalysed hydroformylation, which resulted in a matched com-
bination for ligands with gluco- (ligands 4) and talofuranoside
(ligands 5) backbone (Fig. 2(a)).
Unlike what happens in the hydroformylation process, the
different substituents in the biphenyl moieties have a limited
influence on enantioselectivity (Fig. 4 and Table 4). The effect is
also different: results are better with ligands containing tert-
butyl at both ortho and para positions (ligand 3c) (Fig. 4), while
in the Rh-catalysed hydroformylation reaction the best enantio-
selectivities were obtained with ligands containing methoxy
substituents in the biphenyl moieties (Fig. 2(a)). Ligands with
trimethylsilyl in ortho positions (3d) also provided high enantio-
selectivity (up to >99% (R) at 5 ЊC).
Scheme 4 Allylic alkylation of rac-1,3-diphenylacetoxyprop-1-ene
with compounds 1–5.
The reaction using xylofuranoside diphosphite ligand 1a,
containing two unsubstituted biphenyl moieties, provided low
enantioselectivity (entry 1). Introducing bulky tert-butyl substi-
tuents in the ortho and para positions of both biphenyl moieties
(ligand 1c) had a strong positive effect on enantioselectivity
(entry 2), which increased from 20 to 90% ee. Furthermore, the
tert-butyl groups also had a positive effect on activity (entry 1
vs. entry 2).
Finally, if we compare the results for ligands 3e,f (Table 4),
which contain stereogenic binaphthyl moieties, we can see
that the sense of the enantiodiscrimination is predominantly
controlled by the configuration of the biaryl at the phos-
phite moieties. Accordingly, ligands containing (S)-binaphthyl
moieties gave the (S)-dimethyl 2-methylsuccinate, while ligands
containing (R)-binaphthyl moieties gave the (R) product. This
behaviour was also observed for the hydroformylation reaction.
This set of ligands were also applied in the Rh-catalysed
hydrogenation of other benchmark dehydroamino acid deriv-
atives. The results followed the same trend as observed
for dimethyl itaconate, but the activities were somewhat
higher.2k
When we used ribofuranoside diphosphite ligands 2b,c, the
configuration of the carbon atom C-3 of which is opposite to
the configuration of this atom in ligands 1, enantioselectivities
were very low even for the ligands with the bulky tert-butyl
groups in ortho position (entries 3 and 4). Of these two, the
presence of methoxy groups at the para positions (2b) slowed
the reaction dramatically, whereas the enantioselectivity was
slightly higher.
The reaction using ligand 4a, which is related to 1a but has a
new stereogenic centre at C-5 with (R) configuration, provided
only 9% ee (entry 8). As with ligand 1c, the presence of bulky
tert-butyl groups in the ortho-positions of the biphenyl moiety
(ligands 4b and 4c) had a positive effect on enantioselectivity
and activity (entry 8 vs. entries 9 and 10). Also, the presence of
methoxy groups in the para positions of the biphenyl moieties
significantly improved enantioselectivity (ee up to 95%, entry
9).
The trends were similar with ligands 3, in which the con-
figuration of the carbon atom C-3 is opposite to those of
ligands 4, but enantioselectivities and activities were lower
(entries 5–7).
The use of ligand 5c, which resulted from changing the con-
figuration of C-5 in ligands 3 from (R) to (S), led to lower
activity and slightly lower enantioselectivity than the catalytic
system Pd/3 (entry 11 vs. entry 7).
Allylic substitution
The palladium-mediated allylic substitution reaction is an effi-
cient synthetic tool for the formation of carbon–carbon and
carbon–heteroatom bonds, which is one of the main objectives
in modern organic synthetic chemistry.16 The combination of
mixed phosphite–oxazoline,2e phosphite–thioether17 and phos-
phite–phosphine18 ligands has been successfully used in the
Pd-catalysed allylic substitution, but studies using diphosphite
ligands are scarce.2g,h
In this section we describe the results with the modular
furanoside ligands 1–5, which, to the best of our knowledge,
constituted the first example of diphosphite ligands being
applied to this process.2g,h
Table 5 shows the yield and enantiomeric excess obtained in
the palladium(0)-catalysed addition of dimethyl malonate to
rac-1,3-diphenylacetoxyprop-1-ene (Scheme 4).19 This reaction
was chosen as a model because it has been carried out with a
wide variety of ligands carrying different donor groups. This
enables us to directly compare the efficacy of several ligand
systems.
Finally, ligands 1 and 2 were tested in the palladium-cata-
lyzed reaction of 1,3-diphenyl-2-propenyl acetate with benzyl-
amine as a model reaction of the allylic amination (Scheme 5).2h
In general, the results follow the same trend as that observed for
the allylic alkylation, which is not unexpected because the reac-
tions have a similar mechanism.20 However, the enantiomeric
excesses obtained are higher (up to 97% ee), and the reaction
rates are much lower.2h The higher ee’s in the allylic amination
can be explained by a later transition state, which results in
larger ligand–allyl interaction.21
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were 4b,d and 5b,d, with RR and SS configuration of C-3 and
C-5, respectively. The best ligands for hydrogenation were 3c,d
with R configuration of both C-3 and C-5. Finally, the best
ligands for allylic substitution were 1c and 4b,c. This shows the
advantage of the modular carbohydrate ligands described in
this study. The many combinations they offer were the key to
finding the most suitable ligand for each particular process.
Scheme 5 Allylic aminaion of rac-1,3-diphenylacetoxyprop-1-ene
with compounds 1, 2.
The results obtained with ligands 1–5 clearly indicated that
stereogenic centre C-5 scarcely affected the enantioselectivity.
This suggests that the nucleophilic attack, which is generally
accepted as the enantiodiscrimination step,16,20 takes place trans
toward the carbon atom C-5 (Fig. 5). We obtained further
proof for this hypothesis by studying a series of heterodonor
phosphite–thioether and phosphite–phosphine ligands with the
same furanoside backbone, where the nucleophilic attack also
occurs cis to the phosphite moiety at C-3.2h
Acknowledgements
We thank the Spanish Ministerio de Educación y Cultura and
the Generalitat the Catalunya (CIRIT) for financial support.
References
1 See, for example: (a) H. Brunner and W. Zettlmeier, in Handbook of
Enantioselective Catalysis, VCH, Weinheim, 1993; (b) R. Noyori, in
Asymmetric Catalysis in Organic Synthesis, Wiley, New York, 1994;
(c) Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley, New York,
2000; (d ) Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen,
A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999, vol. 1.
2 See, for example: (a) J. E. Babin and G. T. Whiteker (Union Carbide
Chem. Plastics Techn. Co.), World Pat., WO 93/03839, 1993; (Chem.
Abstr., 1993, 119, P159872h); (b) G. J. H. Buisman, L. A. van deer
Veen, A. Klootwijk, W. G. J. de Lange, P. C. J. Kamer, P. W. N. M.
van Leeuwen and D. Vogt, Organometallics, 1997, 16, 2929;
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3 (a) M. J. Baker and P. G. Pringle, J. Chem. Soc., Chem. Commun.,
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Fig.
5
Nucleophilic attack on the palladium diphosphite allyl
intermediate (R3 = H, CH3).
In summary, the enantiomeric excesses with ligands 1–5 in
the asymmetric allylic substitution depend strongly on the
absolute configuration of the stereocentre carbon C-3 of
the carbohydrate backbone. This behavior is similar to the
results obtained for asymmetric hydrogenation, except that the
stereochemistry in the carbon atom C-3 that provides good
enantioselectivities is reversed. For asymmetric hydrogenation,
therefore, the enantioselectivities were best with ligands 3, while
ligands 1 and 4 provided the highest enantiomeric excess in
asymmetric allylic alkylation. Note that introducing a stereo-
genic centre in C-5 had a positive effect on activity, although the
enantioselectivity is unaffected. This contrasts with the results
from the hydroformylation and hydrogenation reactions where
the new stereogenic centre at C-5 improved both activities and
enantioselectivities. All these results show that the modular
carbohydrate ligands described in this study have several
advantages for optimising the selectivities (activity and enantio-
selectivity) for each particular process.
4 For representative examples of successful modifications of
phosphite ligands for asymmetric catalysis, see refs. 2a,b,i and j.
5 See also, for example: (a) T. V. RajanBabu and A. L. Casalnuovo,
Pure Appl. Chem., 1994, 94, 149; (b) D. S. Clyne, Y. C. Mermet-
Bouvier, N. Nomura and T. V. RajanBabu, J. Org. Chem., 1999, 64,
7601; (c) K. Yonehara, K. Ohe and S. Uemura, J. Org. Chem., 1999,
64, 937; (d ) H. Park and T. V. RajanBabu, J. Am. Chem. Soc., 2002,
124, 734; (e) R. J. Selke, Organomet. Chem., 1989, 370, 249; ( f ) T. V.
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and J. C. Calabrese, J. Org. Chem., 1999, 64, 3429; (g) M. Diéguez,
A. Ruiz and C. Claver, Chem. Commun., 2001, 2702.
Conclusions
6 (a) M. Diéguez, A. Ruiz and C. Claver, Tetrahedron: Asymmetry,
2001, 12, 2895; (b) M. Diéguez, O. Pàmies, A. Ruiz and C. Claver,
Tetrahedron: Asymmetry, 2002, 13, 83; (c) M. Diéguez, O. Pàmies,
A. Ruiz and C. Claver, New. J. Chem., 2002, 26, 827.
7 G. J. H. Buisman, M. E. Martin, E. J. Vos, A. Klootwijk, P. C. J.
Kamer and P. W. N. M. van Leeuwen, Tetrahedron: Asymmetry,
1995, 6, 719.
We have discussed a family of simple and highly modular
furanoside diphosphite ligands for enantioselective catalysis.
These ligands have two main advantages: (1) they can be
prepared in a few steps from readily available -(ϩ)-xylose and
-(ϩ)-glucose and (2) their modular nature allows a facile sys-
tematic variation in the configuration of the stereocentres at the
ligand bridge and in the biaryl substituents. This means that it is
possible to select a ligand for each particular reaction that pro-
vided enantioselectivities that are comparable to those of the
best catalysts previously reported in different asymmetric
reactions.
Varing the chirality of the sugar backbone stereocentres (C-3
and C-5) and the biaryl moieties in these ligands had a remark-
able effect on activity and selectivity in several types of asym-
metric catalytic reactions. We found that, for the same series of
ligands the effects were completely different depending on the
reaction studied. Thus, the best ligands for hydroformylation
8 O. Pàmies, G. Net, A. Ruiz and C. Claver, Tetrahedron: Asymmetry,
2000, 11, 1097.
9 (a) M. Beller, B. Cornils, C. D. Frohning and C. W. Kohlpainter,
J. Mol. Catal., 1995, 104, 17; (b) F. Agboussou, J.-F. Carpentier and
A. Mortreux, Chem. Rev., 1995, 95, 2485; (c) S. Gladiali, J. C. Bayón
and C. Claver, Tetrahedron: Asymmetry, 1995, 7, 1453; (d ) Rhodium
Catalyzed Hydroformylation, ed. P. W. N. M. van Leeuwen and
C. Claver, Kluwer Academic Press, Dordrecht, 2000.
10 The catalysts were prepared in situ during 16 h. In general,
hydrogenated or polymerized products of styrene were not
observed.
11 M. Diéguez, O. Pàmies, A. Ruiz, S. Castillón and C. Claver,
Chem. Commun., 2000, 1607.
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12 Ligands 3d and 4d gave 52% (R) and 90% (S) ee at 20 ЊC,
respectively.
13 Calculated from the HP-NMR data using the typical value of the cis
and trans phophorus–proton coupling constants as in ref. 2f and
P. W. N. M. van Leeuwen, P. C. J. Kamer, J. N. H. Reek and
P. Dierkes, Chem. Rev., 2000, 100, 2741.
14 Recent mechanistic studies suggest that the enantioselectivity is
determined during the insertion of the olefin into the Rh–H bond,
see for example: (a) D. Gleich, R. Schmid and W. A. Herrmann,
Organometallics, 1998, 17, 2141; (b) T. Horiuchi, E. Shirakawa,
K. Nozaki and H. Takaya, Organometallics, 1997, 16, 2921 and ref.
2c.
17 K. Selvakumar, M. Valentini, P. S. Pregosin and A. Albinati,
Organometallics, 1999, 18, 4591.
18 S. Deerenberg, H. S. Schrekker, G. P. F. Van Strijdonck, P. C. J.
Kamer, P. W. N. M. van Leeuwen and K. Goubitz, J. Org. Chem.,
2000, 65, 4810.
19 The reactions were carried out in dichloromethane at room
temperature in the presence of a catalyst generated in situ from
π-allyl–palladium chloride dimer [PdCl(η3-C3H5)]2 and the corre-
sponding ligand and a catalytic amount of KOAc.
20 (a) B. M. Trost and D. L. van Vranken, Chem. Rev., 1996, 96, 395;
(b) M. Johannsen and K. A. Jorgensen, Chem. Rev., 1998, 98,
1869.
15 In general, the catalysts were prepared in situ by adding the
corresponding ligands to the catalyst rhodium precursor
[Rh(cod)2]BF4.
16 J. Tsuji, in Palladium Reagents and Catalysis, Innovations in Organic
Synthesis, Wiley, New York, 1995.
21 (a) P. Dierkes, S. Ramdeehul, L. Barloy, A. de Cian, J. Fischer,
P. C. J. Kamer, P. W. N. M. van Leeuwen and J. A. Osborn,
Angew. Chem., Int. Ed. Engl., 1993, 32, 566; (b) S. Ramdeehul,
P. Dierkes, R. Aguado, P. C. J. Kamer, P. W. N. M. van Leeuwen and
J. A. Osborn, Angew. Chem., Int. Ed., 1998, 37, 3118.
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