New types of soluble polymer-supported bisphosphine ligands with a cyclobutane backbone for Pd-catalyzed enantioselective allylic substitution reactions

Article abstract of DOI:10.1002/chem.200400488

A highly efficient and practical optical resolution of anti head-to-head racemic coumarin dimer 7 has been achieved by molecular complexation with TADDOL, (-)-8, through a hydrogen bonding interaction to afford the corresponding two enantiomers, (-)- and (+)-7, in 70 and 75% yields, respectively, with >99% ee. Starting from enantiopure (-)-7, a new type of C₂-symmetric bisphosphine ligand (S,S,S,S)-3 with a cyclobutane backbone has been synthesized in good yield by facile transformations. The asymmetric induction efficiency of these chiral bisphosphine ligands in Pd-catalyzed asymmetric allylic substitution reactions was evaluated. Under the experimental conditions, the allylic substitution products could be obtained in excellent yields (up to 99%) and enantioselectivities (up to 98.9% ee). By taking advantage of the high enantioselectivity of this catalytic reaction and the easily derivable carboxylate groups on the cyclobutane backbone of ligand (S,S,S,S)-3, a new type of analogous ligand (S,S,S,S)-4 as well as the MeO-PEG-supported soluble ligand (S,S,S,S)-5 (PEG = polyethylene glycol) have also been synthesized and utilized in asymmetric allylic substitution reactions. In particular, the MeO-PEG supported (S,S,S,S)-5b had a synergistic effect on the enantioselectivity of the reaction compared with its nonsupported precursor (S,S,S,S)-4c, affording the corresponding allylation products 14a and 14b with excellent enantioselectivities (94.6 and 97.2% ee, respectively). Moreover, the Pd complex of (S,S,S,S)-5b could easily be recovered and recycled several times without significant loss of enantioselectivity and activity in the allylic substitution reactions.

Full text of DOI:10.1002/chem.200400488

FULL PAPER
New Types of Soluble Polymer-Supported Bisphosphine Ligands with a
Cyclobutane Backbone for Pd-Catalyzed Enantioselective Allylic
Substitution Reactions
Dongbo Zhao, Jie Sun, and Kuiling Ding*[a]
Dedicated to Professor Changtao Qian on the occasion of his 70th birthday
Abstract: A highly efficient and practi-
cal optical resolution of anti head-to-
head racemic coumarin dimer 7 has
been achieved by molecular complexa-
tion with TADDOL, (À)-8, through a
hydrogen bonding interaction to afford
the corresponding two enantiomers,
(À)- and (+)-7, in 70 and 75% yields,
respectively, with >99% ee. Starting
from enantiopure (À)-7, a new type of
the experimental conditions, the allylic
substitution products could be obtained
in excellent yields (up to 99%) and
enantioselectivities (up to 98.9% ee).
By taking advantage of the high enan-
tioselectivity of this catalytic reaction
and the easily derivable carboxylate
groups on the cyclobutane backbone of
ligand (S,S,S,S)-3, a new type of analo-
gous ligand (S,S,S,S)-4 as well as the
MeO-PEG-supported soluble ligand
(S,S,S,S)-5 (PEG=polyethylene glycol)
have also been synthesized and utilized
in asymmetric allylic substitution reac-
tions. In particular, the MeO-PEG sup-
ported (S,S,S,S)-5b had a synergistic
effect on the enantioselectivity of the
reaction compared with its nonsupport-
ed precursor (S,S,S,S)-4c, affording the
corresponding allylation products 14a
and 14b with excellent enantioselectivi-
ties (94.6 and 97.2% ee, respectively).
Moreover, the Pd complex of (S,S,S,S)-
5b could easily be recovered and recy-
cled several times without significant
loss of enantioselectivity and activity in
the allylic substitution reactions.
C2-symmetric
bisphosphine
ligand
(S,S,S,S)-3 with a cyclobutane back-
bone has been synthesized in good
yield by facile transformations. The
asymmetric induction efficiency of
these chiral bisphosphine ligands in Pd-
catalyzed asymmetric allylic substitu-
tion reactions was evaluated. Under
Keywords: allylic substitutions
·
asymmetric catalysis · bisphosphine ·
immobilization · optical resolution ·
P
ligands
· palladium · soluble
polymers
Introduction
The asymmetric catalysis of organic reactions to provide
enantiomerically enriched products is of central importance
to modern synthetic and pharmaceutical chemistry.[1] The
development of chiral ligands is crucial if high enantioselec-
tivity of catalytic asymmetric reactions is to be achieved.[2]
Therefore, the design of novel chiral ligands has been an
eternal theme in the research of asymmetric catalysis. Be-
cause some C2-symmetric bisphosphine ligands (such as
BINAP[3] and Trostꢀs ligand (1)[4]) have shown excellent
asymmetric induction in many kinds of asymmetric reac-
tions, we are interested in the development of a new type of
C2-symmetric bisphosphine ligand (3), which has a cyclobu-
tane backbone and carboxylate functional groups and which
can be considered an analogue of 1 and 2.[5] Herein, we
report the synthesis of bisphosphine ligands 3 and 4 and
their polyethylene glycol(PEG)-supported derivatives 5, as
well as their application in Pd-catalyzed asymmetric allylic
substitution reactions.[6] Meanwhile, an efficient and practi-
cal resolution of anti head-to-head racemic coumarin dimer
[a] D. Zhao, J. Sun, Prof. K. Ding
State Key Laboratory of Organometallic Chemistry Shanghai Insti-
tute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (China)
Fax : (+86)21-6416-6128
E-mail: kding@mail.sioc.ac.cn
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5952 – 5963
(Æ)-7 has also been achieved by molecular complexation
with (R,R)-(À)-trans-4,5-bis(hydroxydiphenylmethyl)-2,2-di-
methyl-1,3-dioxacyclopentane (TADDOL, (À)-8) to give
enantiopure 7, a key intermediate in the synthesis of 3–5.
available,[10] as a chiral host to resolve the two enantiomers
of 7 by molecular complexation through hydrogen bonding.
Thus, by heating a mixture of an equimolar amount of (Æ)-
7 and the resolving agent (À)-8 in ethyl acetate and then
cooling the homogeneous solution to room temperature mo-
lecular crystals of (À)-8 and (À)-7 were formed with (À)-7
in 88.3% ee. The crystals that precipitated were collected by
filtration and washed with ethyl acetate; these crystals were
characterized as 2:1 molecular crystals of (À)-8 and (À)-7
Results and Discussion
Practical optical resolution of anti head-to-head racemic
coumarin dimer (Æ)-7: As shown in Scheme 1, the prepara-
tion of anti head-to-head racemic coumarin dimer (Æ)-7 was
1
by H NMR spectroscopy. The enantiomeric excess of the
opposite enantiomer [(+)-7] remaining in the mother liquor
was 81.7%. Further recrystallization of the molecular crys-
tals (À)-7·[(À)-8]2 from ethyl acetate afforded enantiopure
(À)-7·[(À)-8]2 in 70% yield. Decomposition of the molecu-
lar crystals (À)-7·[(À)-8]2 with DMF gave (À)-7 in 99%
yield. The absolute configuration of (À)-7 was assigned as
S,S,S,S by comparison of its optical rotation with that report-
ed in the literature.[9a] The enantiomeric excess of (+)-7 in
the mother liquor could be further enriched to 99% by fur-
ther recrystallization from ethanol and then recyclization in
AcOH.
Synthesis of bisphosphine ligands (S,S,S,S)-3a–h with a cy-
clobutane backbone: With the enantiopure 7 in hand, we ex-
tended its application to the synthesis of a new type of C2-
symmetric bisphosphine ligand 3. As shown in Scheme 2,
heating an ethanolic solution of (S,S,S,S)-7 resulted in lac-
tone ring-opening to give ethyl ester (S,S,S,S)-9a in quantita-
tive yield. Treatment of (S,S,S,S)-9a with (CF3SO2)2O in the
presence of Et3Ngave the ditriflate derivative ( S,S,S,S)-10a
in 97.3% yield. Compound (S,S,S,S)-10a underwent a cou-
pling reaction with diarylphosphine oxides in the presence
of Pd(OAc)2/dppp (dppp=1,3-bis(diphenyl-phosphino)pro-
pane) and diisopropylethylamine to give the corresponding
1,2-bis(2-diarylphosphinoylphenyl)cyclobutane derivatives
(S,S,S,S)-11a–f in good-to-excellent yields. The target bi-
sphosphine ligands (S,S,S,S)-3a–f could be easily obtained
by the reduction of their oxides (S,S,S,S)-11a–f with HSiCl3
in the presence of N,N-dimethylaniline in 74–91% yields.
Two analogous ligands (S,S,S,S)-3g,h were also designed
and synthesized following a similar procedure to that used
for the preparation of (S,S,S,S)-3a–f. As shown in Scheme 2,
the preparation of methyl ester derivative (S,S,S,S)-3g was
quite simple and the total yield from the enantiopure cou-
marin dimer was >70%. In contrast, the coupling reaction
of benzyl ester (S,S,S,S)-10c with diphenylphosphine oxides
in the presence of Pd(OAc)2/dppp produced a lot of benzyl-
diphenylphosphine oxide (PhCH2P(O)Ph2) in addition to
the expected phosphine oxide (S,S,S,S)-11h. The total yield
Scheme 1. Optical resolution of coumarin dimer 7 by molecular complex-
ation with TADDOL (À)-8.
carried out by following a literature method;[7] coumarin 6
was irradiated in benzene solution in the presence of benzo-
phenone as a sensitizer to give (Æ)-7 in >90% yield
(0.2 mol scale). Although the optical resolution of (Æ)-7
could be achieved by stepwise recrystallization of its diaster-
eomers formed with enantiopure a-phenylethylamine, acidic
hydrolysis, and recyclization of the hydroxy carboxylic
acid,[8] the process is somewhat convoluted. The direct syn-
thesis of enantiopure (S,S,S,S)-7 through topochemically
controlled [2+2] photodimerization of coumarin 6 included
in a TADDOL ((À)-8) host in the solid state or in an aque-
ous suspension was recently reported by Toda and co-work-
ers to give (À)-(S,S,S,S)-7 in 99% yield with 100% ee.[9] De-
spite the difficulties associated with the large-scale prepara-
tion of (À)-(S,S,S,S)-7 by using this strategy, the perfect mo-
lecular recognition between (À)-8 and (À)-7 in the product
prompted us to utilize TADDOL (À)-8, which is readily
À
for the last two steps including C P bond formation and
HSiCl3 reduction of the phosphine oxide was only 30%.
Application of bisphosphine ligands (S,S,S,S)-3a–f in Pd-cat-
alyzed enantioselective allylic substitution: Pd-catalyzed
enantioselective allylic substitution is one of the most impor-
À
À
tant C C or C Nbond-forming reactions in modern asym-
metric catalysis.[4,11] To demonstrate the asymmetric induc-
tion efficiency of the chiral ligands (S,S,S,S)-3a–f, Pd-cata-
lyzed enantioselective allylic substitution was taken as the
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[(S,S,S,S)-3a–f] showed excel-
lent asymmetric induction in
the model reaction to give the
corresponding allylation prod-
ucts in 91–99% yield and with
95.6–98.9% ee. These results
clearly demonstrate that this
type of bisphosphine ligands
(S,S,S,S)-3a–f with cyclobutane
backbone are very promising in
asymmetric catalysis.
The use of this catalyst
system was extended to the al-
lylic substitution of cyclic sub-
strate 15[11e–h]; the reaction pro-
ceeded smoothly to give the
corresponding cyclic allylation
products 16a and 16b in good
yields (74–85%) and enantiose-
lectivities (73.2–87.5% ee) by
using 5 mol% of the catalyst
(Scheme 3). These results com-
bined with those obtained
above indicate that this type of
Scheme 2. Transformation of enantiopure coumarin dimer (S,S,S,S)-7 to a new type of chiral bisphosphine li-
gands (S,S,S,S)-3a–h: a) Ar=C6H5, R=Et; b) Ar=4-MeOC6H4, R=Et; c)Ar=4-tBuC6H4, R=Et; d) Ar=3-
MeC6H4, R=Et; e) Ar=3,5-(Me)2C6H3, R=Et; f) Ar=4-MeC6H4, R=Et; g) Ar=C6H5, R=Me; h) Ar=
C6H5, R=Bn.
model reaction. Accordingly, 1,3-diphenylprop-2-enyl ace-
tate (12) was employed as the substrate, and dimethyl malo-
nate 13a or benzylamine 13b was utilized as the nucleo-
phile. As shown in Table 1, all of the chiral ligands
Table 1. Pd-catalyzed enantioselective allylic substitution reactions using
bisphosphine ligands 3a–f.[a]
Scheme 3. Pd-catalyzed enantioselective allylic substitution reactions of
cyclohex-2-enyl acetate using bisphosphine ligand (S,S,S,S)-3a.
Entry
Ligand
Base
NuH
Product
Yield
[%][b]
ee
ligand is particularly useful in Pd-catalyzed allylic substitu-
tion reactions, which encouraged us to further investigate
their structure–property relationship and immobilization in
asymmetric catalysis.
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
3a
3b
3c
3c
3d
3e
3 f
3a
3b
3c
3d
3e
3 f
BSA
13a
13a
13a
13a
13a
13a
13a
13b
13b
13b
13b
13b
13b
14a
14a
14a
14a
14a
14a
14a
14b
14b
14b
14b
14b
14b
99
99
99
99
99
99
99
99
91
97
96
94
91
96.8
98.0
97.5
98.9
96.1
97.3
95.8
95.6
96.2
96.2
96.4
96.7
97.5
BSA[d]
BSA[d]
BSA
BSA[d]
The impact of carboxylate groups on the enantioselectivity
of the allylic substitutions: The investigation into the rela-
tionship between the carboxylate groups on the cyclobutane
backbone of the bisphosphine ligands and the enantioselec-
tivity of the reaction will provide useful information regard-
ing their immobilization on an organic polymer support by
taking advantage of the easily derivable carboxylic groups.
To investigate the impact of the ester groups of the chiral li-
gands 3 on their asymmetric induction, ligands (S,S,S,S)-3a
or (S,S,S,S)-3g,h were submitted to Pd-catalyzed enantiose-
lective allylic substitution of 12 with dimethyl malonate 13a
and benzylamine 13b, respectively, under the optimized con-
ditions indicated in Table 1. As shown in Figure 1, the enan-
BSA[d]
BSA[d]
–
–
–
–
–
–
[a] The molar ratio of 12/NuH/[{(h-allyl)PdCl}2] /3=1:2:0.025:0.06. All
the ligands 3a–f used were of the S,S,S,S configuration. [b] Yield of isolat-
ed product. [c] The enantiomeric excesses were determined by HPLC on
a Chiralcel OJ or AD column. The absolute configurations of 14a and
14b were assigned as S and R, respectively, based on their optical rota-
tions. [d] BSA (2 equiv) was added in the presence of LiOAc (5 mol%).
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Bisphosphine Ligands in Pd-Catalyzed Allylic Substitution Reactions
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X-ray crystal structural analysis (Figure 2).[12] The molecule
of (S,S,S,S)-4a adopts a C2-symmetric geometry. Evidently,
the two chelating phosphorus atoms in the ligand have a
Figure 1. The influence of the ester groups of the ligands 3 on the enan-
tioselectivities of Pd-catalyzed allylic substitution reactions of 12 with di-
methyl malonate 13a (dotted line) and benzylamine 13b (solid line).
Figure 2. Molecular structure of (S,S,S,S)-4a (ORTEP drawing; 30%
probability thermal ellipsoids).
tioselectivities of both reactions dramatically decreased as
the size of the ester groups was increased. When the bis-
phosphine ligand (S,S,S,S)-3h, which contains benzyl ester
groups on the cyclobutane backbone, was used, the enantio-
selectivities of the reactions dropped to around 80%. This
substituent effect on the enantioselectivities of the reactions
might cause a reduction in the enantioselectivity of the reac-
tion when this type of ligand is immobilized on a large poly-
mer support by the formation of an ester link. Therefore, we
decided to investigate the effect of modifying the ligands by
reducing the carboxylate groups to hydroxymethyl moieties
((S,S,S,S)-4a–c), which can also be easily immobilized on a
polymer support containing a carboxylic group.
trans configuration. The distance between them is 7.673 Š.
There is no intramolecular hydrogen-bonding interaction be-
tween the two trans-hydroxymethyl groups. The reaction of
(S,S,S,S)-4a with an excess of acetic acid or benzoic acid in
the presence of 4-dimethylaminopyridine (DMAP) using di-
cyclohexylcarbodiimide (DCC) as condensation reagent af-
forded the corresponding acetate and benzoate derivatives
(S,S,S,S)-4d and -4e in 81 and 85% yields, respectively. Sim-
ilarly, (S,S,S,S)-4 f could be obtained from (S,S,S,S)-4c in
85% yield.
Synthesis of analogous bisphosphine ligands (S,S,S,S)-4a–f
with a cyclobutane backbone and their application in enan-
tioselective allylic substitutions: As shown in Scheme 4, the
As summarized in Table 2, the analogous bisphosphine li-
gands (S,S,S,S)-4a–f showed good to excellent asymmetric
induction in PdII-catalyzed allylic substitution reactions with
similar activities to those of (S,S,S,S)-3a–h when the ligands
contain hydroxymethyl ((S,S,S,S)-4a—-c) or carboxylate
groups ((S,S,S,S)-4d–f) on the cyclobutane backbone. The
absolute configurations of the products obtained using li-
Table 2. Pd-catalyzed enantioselective allylic substitution reactions using
bisphosphine ligands 4.[a]
Entry
Ligand
Base
NuH
Product
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4 f
4a
4b
4c
4d
4e
4 f
BSA[d]
13a
13a
13a
13a
13a
13a
13b
13b
13b
13b
13b
13b
14a
14a
14a
14a
14a
14a
14b
14b
14b
14b
14b
14b
81.3
>99
>99
>99
>99
>99
>99
90.3
>99
>99
66.5
78.8
86.8
80.9
90.8
89.9
81.8
89.3
84.7
88.1
87.0
96.4
98.7
90.7
BSA[d]
BSA[d]
BSA[d]
BSA[d]
BSA[d]
–
–
–
–
–
–
Scheme 4. Modification of bisphosphine ligands by reduction of ethoxy-
carbonyl groups followed by esterification.
10
11
12
[a] The molar ratio of 12/NuH/[h-allylPdCl]2/4=1:2:0.025:0.06. All the li-
gands 4a–f used were of S,S,S,S configuration. [b] Yield of isolated prod-
uct. [c] The enantiomeric excesses were determined by HPLC on a Chir-
alcel OJ or AD column. The absolute configurations of 14a and 14b
were assigned as S and R, respectively, based on their optical rotations.
[d] BSA (2 equiv) was added.
reduction of ethoxycarbonyl functional groups in (S,S,S,S)-
3a–c using LiAlH4 resulted in the formation of the corre-
sponding hydroxymethyl analogues (S,S,S,S)-4a–c in 85–
99% yields. The structure of (S,S,S,S)-4a was confirmed by
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K. Ding et al.
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gands (S,S,S,S)-4a–f were the same as those attained with li-
gands (S,S,S,S)-3a–h, which illustrates that the substituents
on the cyclobutane backbone only have a small impact on
the sign of the asymmetric induction in the catalysis. The
protection of hydroxy groups of (S,S,S,S)-4a with acetate
could improve the enantioselectivities of the allylic substitu-
tion reactions (Table 2, en-
for use in Pd-catalyzed enantioselective allylic substitution
by using polyethylene glycol monomethyl ether (MeO-
PEG) as the support.
As shown in Scheme 5,
a MeO-PEG based-support
(MeO-PEG-O2CCH2CH2CO2H, 18) containing a carboxylic
acid end group was prepared by the reaction of MeO-PEG
tries 1, 7 versus 4, 10, respec-
tively), particularly when using
benzylamine as the nucleophile.
The performance of the ben-
zoate derivative (S,S,S,S)-4e
was inferior to that of the ace-
tate
analogue
(S,S,S,S)-4d
(Table 2, entry 5 versus 4), al-
though the enantioselectivity of
allylic amination could be as
high as 98.7% using (S,S,S,S)-
4e, which has a relatively low
catalytic
activity
(Table 2,
entry 11). Therefore, acetate
might be an ideal protecting
group in the PEG-supported Scheme 5. Synthesis of MeO-PEG-supported bisphosphine ligands (S,S,S,S)-5a–d.
ligand (S,S,S,S)-5. The conven-
ient preparation of ligands
(S,S,S,S)-4a and (S,S,S,S)-4c and their facile esterification as
well as the synergistic effect of the ester groups of the li-
gands on the enantioselectivity of the reactions have provid-
ed an excellent opportunity for anchoring the hydroxymeth-
yl ligands (S,S,S,S)-4a–c on polymeric supports that possess
carboxylic acid functional groups.
(Mn =2000, 17) with succinic anhydride in the presence of
[15i]
Et3Naccording to the literature procedure.
The conden-
sation of support 18 with (S,S,S,S)-4a or -4c in the presence
of DCC/DMAP as condensation reagent afforded the mono-
ester (S,S,S,S)-5a or (S,S,S,S)-5b in 79 and 89% yields, re-
spectively. An excess (5 equiv) of (S,S,S,S)-4a or (S,S,S,S)-4c
was employed to ensure the complete conversion of support
18 and a 1:1 ratio of support and bisphosphine unit in the
anchored (S,S,S,S)-5a and (S,S,S,S)-5b. The separation and
purification of (S,S,S,S)-5a and (S,S,S,S)-5b was quite con-
venient. After removal of dicyclohexylurea (DCU), which
was formed in the reaction, by simple filtration, the filtrate
was concentrated to dryness under reduced pressure, and
then a minimum amount of dichloromethane was added to
the crude product to ensure the complete dissolution of the
residue. Addition of diethyl ether allowed the precipitation
of supported ligands (S,S,S,S)-5a or (S,S,S,S)-5b as white
solids. This procedure was repeated three times to guarantee
products of high purity. Their 1H NMR, 31P NMR, and
MALDI-TOF spectra (Figure 3) were consistent with the
expected structures and demonstrated the high purity of the
ligands (S,S,S,S)-5a and (S,S,S,S)-5b. The unreacted starting
hydroxymethyl derivatives, (S,S,S,S)-4a and (S,S,S,S)-4c,
were readily recovered from the filtrate by column chroma-
tography on silica gel. The remaining hydroxy group of
(S,S,S,S)-5a and (S,S,S,S)-5b could be further protected with
acetate by the reaction with two equivalents of acetic acid
following the same procedures as those used for the prepa-
ration and purification of (S,S,S,S)-5a and (S,S,S,S)-5b to
afford (S,S,S,S)-5c and (S,S,S,S)-5d in 78 and 74% yields, re-
spectively.
Synthesis of MeO-PEG-supported bisphosphine ligands
(S,S,S,S)-5a–d for enantioselective allylic substitution reac-
tions—homogeneous catalysis and heterogeneous recovery
of the catalyst: Although significant developments in homo-
geneous asymmetric catalysis have been achieved in recent
decades,[1] its application has been limited mainly due to
problems with the separation and recycling of the expensive
chiral catalyst. To overcome these problems, the immobiliza-
tion of homogeneous catalysts on insoluble polymer sup-
ports has received considerable attention, which has made
the recovery and reuse of the catalysts possible, as well as
their adaptation to continuous-flow-type processes.[13] How-
ever, the immobilization of the chiral catalysts on insoluble
supports often results in lower activities and enantioselectiv-
ities than those observed for their homogeneous counter-
parts. Alternatively, homogeneous catalysts can be achieved
by utilizing soluble polymer supports in the immobilization,
and which may have catalytic activities and stereoselectivi-
ties similar to those of the homogeneous parent systems.[14]
When the reaction is completed, the catalyst can be separat-
ed by either solvent or heat precipitation, membrane filtra-
tion or size-exclusion chromatography. Owing to the high
order of asymmetric induction of ligands (S,S,S,S)-4 in Pd-
catalyzed allylic substitution reactions, as well as the easy
modification of hydroxy groups on the cyclobutane back-
bone of the ligands, we decided to prepare a new type of
soluble polymer-supported bisphosphine ligand (S,S,S,S)-5
With the MeO-PEG-supported ligands (S,S,S,S)-5a–
(S,S,S,S)-5d in hand, we next investigated their asymmetric
induction and the impact of the MeO-PEG support on the
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Bisphosphine Ligands in Pd-Catalyzed Allylic Substitution Reactions
5952 – 5963
coupling of the MeO-PEG support to the dihydroxy bis-
phosphine (S,S,S,S)-4c (ligand (S,S,S,S)-5b) significantly im-
proved the enantioselectivities from 90.8 and 87.0% ee to
94.7 and 97.3% ee, respectively (entries 3 and 9 in Table 2
versus entries 2 and 6 in Table 3), which demonstrates the
synergistic effect of the polymeric support on the enantiose-
lectivity of the reaction. On the other hand, the acetate-pro-
tected analogue (S,S,S,S)-5d exhibited reduced enantioselec-
tivity compared with (S,S,S,S)-5b (Table 3, entries 4 and 8
versus entries 2 and 6, respectively). The other advantage of
the present catalyst system is the convenient recovery of the
catalyst. After the reaction was complete, diethyl ether was
added to the reaction mixture and the catalyst precipitated
as a yellow solid. Simple filtration afforded the catalyst in
>90% recovery and the flash chromatography of the fil-
trate conveniently afforded the product.
Recyclablity of the Pd complex of the MeO-PEG-supported
ligand (S,S,S,S)-5b in allylic substitution reactions: On the
basis of the findings mentioned above, we then examined
the reusability of the recovered Pd complex of (S,S,S,S)-5b
in enantioselective allylic alkylation and amination reactions
in order to demonstrate further advantages of this type of li-
gands. After the first run of the reaction, diethyl ether was
added to the reaction mixture so that the catalyst formed a
precipitate which was filtered off under an argon atmos-
phere and washed with diethyl ether three times. The recov-
ered catalyst was submitted to the next catalytic reaction
without any further addition of Pd. The recovered catalyst
could be recycled with only a slight loss in the activity and
enantioselectivity of the allylic alkylation reaction (from
94.6% ee in the first run to 86.0% ee in the fourth run;
Table 4, entries 1–4). In particular, the recovered catalyst
could be reutilized nine times in the allylic amination reac-
tion with high enantioselectivities (89.5–97.2% ee; Table 4,
entries 5–13) although the catalytic activity diminished grad-
ually after the fifth run (Table 4, entries 10–13). These re-
sults demonstrate that the MeO-PEG-bound ligand
Figure 3. MALDI-TOF spectra of MeO-PEG-supported ligands
a) (S,S,S,S)-5a and b) (S,S,S,S)-5c.
enantioselectivity of the Pd-catalyzed allylic substitution of
12 with dimethyl malonate 13a or benzylamine 13b. As
shown in Table 3, ligand (S,S,S,S)-5b gave the best perform-
ance for the reactions in terms of both reactivity and enan-
tioselectivity (Table 3, entries 2 and 6). It is evident that the
Table 4. Recyclability of the Pd complex of (S,S,S,S)-5b in allylic substi-
tution reactions.[a]
Entry
Ligand
Base
NuH
Product
Yield
[%][b]
ee
[%][c]
Table 3. Pd-catalyzed enantioselective allylic substitution reactions using
1[d]
2[d]
3[d]
4[d]
5
6
7
8
9
10
11
12
13
1st
1
4
8
13a
13a
13a
13a
13b
13b
13b
13b
13b
13b
13b
13b
13b
14a
14a
14a
14a
14b
14b
14b
14b
14b
14b
14b
14b
14b
>99
>99
>99
88.3
>99
>99
>99
>99
95.9
>99
63.6
69.0
81.0
94.6
93.8
91.7
86.0
97.2
93.4
89.5
91.0
92.2
91.8
90.5
89.6
91.1
MeO-PEG-supported bisphosphine ligands 5a–d.[a]
2nd
3rd
4th
1 st
2nd
3rd
4th
5th
6th
7th
8th
9th
Entry
Ligand
Base
NuH
Product
Yield
[%][b]
ee
[%][c]
16
<0.5
0.5
<1
1
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5a
5b
5c
5d
BSA[d]
13a
13a
13a
13a
13b
13b
13b
13b
14a
14a
14a
14a
14b
14b
14b
14b
45.4
>99
84.3
61.0
97.8
>99
>99
>99
85.4
94.7
90.1
87.5
96.4
97.3
96.4
90.8
BSA[d]
BSA[d]
BSA[d]
–
–
–
–
2
12
20
30
30
[a] The molar ratio of 12/NuH/[h-allylPdCl]2/5=1:3:0.025:0.06. All the li-
gands 5a–d used were of S,S,S,S configuration. [b] Yield of isolated prod-
uct. [c] The enantiomeric excesses were determined by HPLC on a Chir-
alcel OJ or AD column. The absolute configurations of 14a and 14b
were assigned as S and R, respectively, based on their optical rotations.
[d] BSA (3 equiv) was added.
[a] The molar ratio of 12:NuH:[{(h-allyl)PdCl}2]: (S,S,S,S)-5b=
1:3:0.025:0.06. [b] Yield of isolated product. [c] The enantiomeric excess-
es were determined by HPLC on a Chiralcel OJ or AD column. The ab-
solute configurations of 14a and 14b were assigned as S and R, respec-
tively, based on their optical rotations. [d] BSA (3 equiv) was added.
Chem. Eur. J. 2004, 10, 5952 – 5963
www.chemeurj.org
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5957

K. Ding et al.
FULL PAPER
instrument. MALDI-TOF mass spectra were taken on a PerSeptive Bio-
systems Voyager DE-STR equipped with a 337 nm nitrogen laser. Ele-
mental analyses were performed on an Elemental VARIO EL apparatus.
All the experiments sensitive to moisture or air were carried out under
argon atmosphere using standard Schlenk techniques. Commercial re-
agents were used as received without further purification unless other-
wise noted. Dichloromethane and CH3CNwere freshly distilled from cal-
cium hydride and THF, diethyl ether, and toluene from sodium benzo-
phenone ketyl.
Racemic anti head-to-head coumarin dimer 7: The preparation of the
anti head-to-head racemic coumarin dimer (Æ)-7 was carried out by fol-
lowing a literature method in 0.2 mol scale;[7] coumarin 6 was irradiated
in benzene solution in the presence of benzophenone as a sensitizer.
(S,S,S,S)-5b has the advantage of easy recovery and reutili-
zation in asymmetric allylic substitution reactions in addi-
tion to its facile preparation.
Conclusions
In summary, a highly efficient and practical optical resolu-
tion of anti head-to-head racemic coumarin dimer 7 by mo-
lecular complexation with TADDOL 8 through hydrogen
bonding and a convenient transformation of enantiopure
(À)-7 to a new type of C2-symmetric bisphosphine ligands
(S,S,S,S)-3 have been achieved. The asymmetric induction
efficiency of these chiral bisphosphine ligands in Pd-cata-
lyzed asymmetric allylic substitution reactions was evaluat-
ed. Under the experimental conditions, the allylic substitu-
tion products were obtained in excellent yields (up to 99%)
and enantioselectivities (up to 98.9% ee). By taking advant-
age of the high enantioselectivity of the catalytic reaction
and the easily derivable carboxylate groups on the cyclobu-
tane backbone of ligands 3, a new type of analogous ligands
(S,S,S,S)-4, as well as MeO-PEG-supported soluble ligands
(S,S,S,S)-5 have also been synthesized and utilized in asym-
metric allylic substitution reactions. In particular, the MeO-
PEG support in ligand (S,S,S,S)-5b displayed a synergistic
effect on the enantioselectivity of the reaction compared
with its precursor (S,S,S,S)-4c, affording the corresponding
allylation products 14a and 14b with excellent enantioselec-
tivities (94.6 and 97.2% ee, respectively). Moreover, the Pd
complex of (S,S,S,S)-5b could be easily recovered and recy-
cled several times without significant loss of enantioselectiv-
ity and activity of the allylic substitution reactions. Accord-
ingly, this new strategy for efficient and practical optical res-
olution of anti head-to-head racemic coumarin dimer 7, the
excellent asymmetric induction of the chiral ligands 3–5 de-
veloped on the basis of enantiopure 7, as well as the high
functional capacity of coumarin dimer 7 and bisphosphine li-
gands 3 and 4 disclosed in this work will definitely stimulate
further research on the uses of enantiopure 7 as a privileged
scaffold for the synthesis of various chiral ligands or chiral
polymers for use in asymmetric catalysis or for other as-
pects.
Optical resolution of 7 by molecular complexation with (À)-TADDOL
((À)-8): By heating a mixture of an equimolar amount of (Æ)-7 and the
resolving agent (À)-8 in ethyl acetate and then cooling the homogeneous
solution to room temperature molecular crystals of (À)-8 and (À)-7 were
formed with (À)-7 in 88.3% ee. The crystals that precipitated were col-
lected by filtration and washed with ethyl acetate; these crystals were
characterized as 2:1 molecular crystals of (À)-8 and (À)-7 by 1H N MR
spectroscopy. The enantiomeric excess of the opposite enantiomer ((+)-
7) remaining in the mother liquor was 81.7%. Further recrystallization of
the molecular crystals (À)-7·[(À)-8]2 from ethyl acetate afforded enantio-
pure (À)-7·[(À)-8]2 in 70% yield. (À)-7·[(À)-8]2: m.p. 220–2228C (lit.:[9a]
228–2328C); [a]D21 =À72.0 (c=1.00 in C6H6); [a]24315 =À157.5 (c=1.00 in
C6H6); 1H NMR (300 MHz, CDCl3, TMS): d=1.05 (s, 12H), 3.89–3.95
(m, 8H), 4.60 (s, 4H), 7.10–7.60 (m, 48H) ppm; elemental analysis calcd
(%) for C80H72O12: C 78.41, H 5.92; found: C 78.58, H 5.84.
Treatment of the 1:2 complex (À)-7·[(À)-8]2 (10.00 g) with DMF/H2O
(5:1; 50 mL) gave a 1:1 complex of (À)-8 and DMF as colorless needles
in 99% yield (8.60 g). (À)-8·DMF: M.p. 211–2128C; [a]2D0 =À76.2 (c=
1.02 in C6H6); 1H NMR (300 MHz, CDCl3, TMS): d=1.03 (s, 6H), 3.85
(s, 3H), 4.29 (br, 2H), 4.57 (s, 2H), 7.20–7.60 (m, 20H) ppm; EI-MS
(70 eV): m/z (%): 105 (100), 183 (63), 207 (50), 208 (29), 77 (23), 237
(20), 179 (19), 225 (17); IR (KBr): n=3256, 2929, 2901, 1652, 1495, 1414,
1388, 1370, 1333, 1243, 1221, 1207, 1168, 1102, 1082, 1054, 1016, 886, 769,
743, 701, 667, 641, 561, 507 cmÀ1; elemental analysis calcd (%) for
C34H37NO5: C 75.67, H 6.91, N2.60; found: C 75.66, H 6.86, N2.62.
The filtrate containing optically pure (À)-7 was concentrated under re-
duced pressure to give (À)-7 in quantitative yield. (À)-(S,S,S,S)-7: M.p.
168.5–1698C; [a]D21 =À9.0 (c=1.00 in C6H6); [a]24315 =À65.8 (c=1.00 in
C6H6); 1H NMR (300 MHz, CDCl3, TMS): d=3.85–3.95 (m, 4H), 7.10–
7.40 (m, 8H) ppm; IR (KBr): n=1760, 1490, 1450, 775, 765 cmÀ1. (+)-
(R,R,R,R)-7: M.p. 168.5–1698C; [a]2D1 =+9.0 (c=1.00 in C6H6); [a]42315 =+
65.8 (c=1.00 in C6H6); 1H NMR (300 MHz, CDCl3, TMS): d=3.85–3.95
(m, 4H), 7.10–7.40 (m, 8H) ppm; IR (KBr): n=1760, 1490, 1450, 775,
765 cmÀ1
.
The complex (À)-8·DMF (5.40 g) was dissolved in ethyl acetate (15 mL)
and washed with water (3”8 mL). The organic phase was then dried over
anhydrous sodium sulfate and concentrated under reduced pressure to
give TADDOL (À)-8 in >99% yield. M.p. 195–1968C; [a]2D1 =À87.0 (c=
1.00 in C6H6); [a]24315 =À183.0 (c=1.00 in C6H6); 1H NMR (300 MHz,
CDCl3, TMS): d=1.00 (s, 6H), 3.95 (s, 2H), 4.60 (s, 2H), 7.20–7.60 (m,
20H) ppm; IR (KBr): n=3437, 3211, 3091, 3059, 3025, 2988, 2891, 1494,
1462, 1447, 1382, 1371, 1243, 1222, 1191, 1170, 1096, 1080, 1047, 1016,
889, 759, 740, 698, 666, 639, 554, 507 cmÀ1. The recovered resolving re-
agent could be used directly in the next run of the optical resolution of
(Æ)-7 without any change in its efficiency.
Experimental Section
General considerations: 1H and 13C NMR spectra were recorded in
CDCl3 on a Bruker AM300 spectrometer at 258C. The chemical shifts
are given in ppm with TMS (d=0 ppm) and the residue signal of CDCl3
1
(d=77 ppm) as the internal standards for H and 13C NMR spectroscopy,
respectively. The 31P NMR spectra were recorded on a Bruker AM300 in-
strument in CDCl3 with 85% H3PO4 as the external reference and the
19F NMR spectra were recorded in CDCl3 on a Varian Mercury 300 in-
strument. Melting points were measured on an XT-4 apparatus and are
uncorrected. Optical rotations were measured on a PE-341 automatic po-
larimeter; [a]D values are given in units of 10À1 degcm2 gÀ1. Liquid chro-
matographic analyses were conducted on a JASCO 1580 system. The IR
spectra were measured on a Rio-Rad FTS-185 spectrometer using KBr
pellets. EI and ESI mass spectra were obtained on HP5989A and Mari-
ner LC-TOF spectrometers, respectively. HRMS spectra were deter-
mined on a Kratos Concept, Q-Tof micro or APEXIII 7.0 TESLA FTMS
(À)-(S,S,S,S)-9a: A suspension of the anti head-to-head coumarin dimer
(À)-(S,S,S,S)-7 (5.0 g, 17.1 mmol) in ethanol (160 mL) was refluxed for
48 h. The solution was concentrated and dried in vacuo to obtain the
product (S,S,S,S)-9a as a white solid (6.57 g, 99%). M.p. 159–1618C
(lit.:[9b] 174–1758C); [a]D20 =À129.2 (c=1.01 in CHCl3); 1H
N MR
(300 MHz, CDCl3, TMS): d=0.83 (t, J=7.1 Hz, 6H), 3.05 (br, 1H), 3.71–
3.91 (m, 6H), 4.87 (d, J=8.36 Hz, 2H), 6.66–7.06 (m, 8H), 8.85 (br,
1H) ppm; IR (KBr): n=3341, 3070, 3039, 2981, 2937, 2905, 1691, 1607,
1596, 1507, 1455, 1413, 1373, 1336, 1315, 1281, 1247, 1217, 1186, 1121,
1086, 1035, 936, 864, 855, 754, 732, 642, 471 cmÀ1; the enantiomeric excess
was determined by HPLC on a Chiralcel OJ column by using hexane/2-
5958
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5952 – 5963

Bisphosphine Ligands in Pd-Catalyzed Allylic Substitution Reactions
5952 – 5963
propanol (90:10) as eluent, flow rate=1.2 mLminÀ1, UV detection at l=
220 nm, tR1 =14.8 min (R,R,R,R isomer), tR2 =20.0 min (S,S,S,S isomer).
with brine. The organic phase was dried over Na2SO4, filtered and then
concentrated under reduced pressure. The resulting residue was submit-
ted to chromatographic separation on silica gel using EtOAc as eluent to
give (S,S,S,S)-11a as an amorphous solid (0.74 g, 99%). [a]2D0 =À95.7 (c=
1.01 in CHCl3); 1H NMR (300 MHz, CDCl3, TMS): d=0.86 (t, J=
7.13 Hz, 6H), 2.95 (d, J=4.3 Hz, 2H), 3.72 (q, J=5.8 Hz, 4H), 5.38 (d,
J=4.3 Hz, 2H), 7.00–7.80 (m, 28H) ppm; 31P NMR (121.46 MHz,
CDCl3): d=31.1 ppm; 13C NMR (75 MHz, CDCl3): d=171.19, 142.34,
142.24, 133.16, 133.10, 132.98, 132.57, 132.21, 132.17, 132.08, 132.04,
131.73, 132.61, 131.21, 129.13, 129.00, 128.51, 128.35, 126.31, 126.14, 60.04,
44.80, 42.30, 42.23, 13.79 ppm; IR (KBr): n=3582, 3420, 3056, 2985, 2939,
1709, 1653, 1591, 1438, 1372, 1313, 1232, 1178, 1140, 1116, 1099, 1069,
1033, 998, 769, 753, 736, 725, 697, 554, 546, 511, 490 cmÀ1; EI-MS (70 eV):
m/z (%): 201 (70), 303 (80), 431 (43), 485 (45), 579 (36), 633 (92),679
(100), 680 ([M+], 34),752 (4); HRMS (EI): calcd for C46H42O6P2 [M+]:
752.2457; found: 752.2439.
(À)-(S,S,S,S)-9b: Following the same procedure as described above for
the preparation of (S,S,S,S)-9a, the reaction of (À)-(S,S,S,S)-7 with
MeOH afforded (S,S,S,S)-9b as an amorphous white solid (98% yield).
[a]D20 =À160.0 (c=1.00 in THF); H NMR (300 MHz, CDCl3, TMS): d=
1
3.40 (s, 6H), 4.04 (d, J=8.7 Hz, 2H), 4.96 (d, J=8.7 Hz, 2H), 6.76–7.12
(m, 8H) ppm; IR (KBr): n=3509, 3346, 1725, 1708, 1610, 1595, 1506,
1453, 1436, 1367, 1355, 1336, 1324, 1300, 1264, 1227, 1208, 1187, 1173,
1152, 1136, 1104, 1089, 1029, 896, 763, 750, 479 cmÀ1; EI-MS (70 eV): m/z
(%): 146 (100), 775 (80), 149 (63), 118 (48), 212 (44), 147 (36), 148 (30),
178 (22), 115 (20), 356 ([M]+, 1).
(À)-(S,S,S,S)-9c: Following the same procedure as described above for
the preparation of (S,S,S,S)-9a, the reaction of (À)-(S,S,S,S)-7 with
BnOH using TiCl4 (10 mol%) as a catalyst afforded (S,S,S,S)-9c as a
white solid (84% yield). M.p. 106–1108C; [a]2D0 =À68.4 (c=1.01 in THF);
1H NMR (CDCl3, 300 MHz, TMS): d=2.86 (s, 1H), 4.04 (d, J=9.3 Hz,
2H), 4.60 (d, J=12.3 Hz, 2H), 4.84 (d, J=12.3 Hz, 2H), 5.07 (d, J=
9.0 Hz, 2H), 6.71–7.25 (m, 18H) ppm; EI-MS (70 eV): m/z (%): 91 (100),
146 (95), 118 (61), 79 (32), 108 (27), 147 (26), 77 (22), 107(21); IR (KBr):
n=3053, 2980, 1722, 1605, 1586, 1509, 1477, 1464, 1435, 1369, 1328, 1303,
(À)-(S,S,S,S)-11b: Following the same procedure as described above for
the preparation of (S,S,S,S)-11a, the reaction of (S,S,S,S)-10a with bis(4-
methoxyphenyl)phosphine oxide afforded (S,S,S,S)-11b as an amorphous
a white solid (88% yield). [a]2D0 =À75.9 (c=1.01 in CHCl3); 1H N MR
(300 MHz, CDCl3, TMS): d=0.81 (t, J=6.7 Hz, 6H), 3.04 (d, J=6.7 Hz,
2H), 3.05–3.81 (m, 16H), 5.36 (d, J=6.7 Hz, 2H), 6.87–7.65 (m,
1266, 1216, 1159, 1134, 1093, 1070, 1035, 998, 745, 695, 546, 497, 416 cmÀ1
;
24H) ppm; 31P NMR (121.46 MHz, CDCl3): d=12.5 ppm; 13C
N MR
elemental analysis calcd (%) for C32H28O6: C 75.57, H 5.55; found: C
75.31, H 5.49.
(75 MHz, CDCl3): d=171.19, 162.10, 162.06, 162.02, 142.39, 142.29,
133.94, 133.79, 133.48, 133.03, 132.83, 132.12, 131.72, 131.74, 129.13,
129.00, 126.10, 125.93, 125.02, 124.85, 123.56, 123.39, 113.93, 113.76, 59.86,
55.16, 44.72, 42.21, 42.14, 29.52, 14.00, 13.80 ppm; IR (KBr): n=3423,
3063, 2976, 2840, 1720, 1598, 1570, 1504, 1464, 1442, 1407, 1369, 1338,
1296, 1255, 1177, 1118, 1025, 935, 830, 801, 757, 729, 664, 622, 551,
458 cmÀ1; EI-MS (70 eV): m/z (%): 261 (100), 363 (62), 575 (41), 611
(66), 612 (27), 700 (46), 799 (82), 800 (37),872 (8); HRMS (EI): calcd for
C50H50O10P2 [M+]: 872.2880; found: 872.2879.
(À)-(S,S,S,S)-10a:
Trifluoromethanesulfonic
anhydride
(0.41 mL,
2.4 mmol) was slowly added to
a
solution of (S,S,S,S)-9a (0.384 g,
1.0 mmol) and Et3N(0.675 mL, 4.8 mmol) in dried CH 2Cl2 (3 mL) at
À788C. The reaction mixture was stirred for 1 h, and then warmed to
room temperature. After the removal of the solvent under reduced pres-
sure, the resulting residue was submitted to chromatographic separation
on silica gel using hexane/EtOAc (5:1) as eluent to give (S,S,S,S)-10a as
a
white solid (0.63 g, 97%). M.p. 73–758C; [a]2D0 =À59.7(c=1.00 in
(À)-(S,S,S,S)-11c: Following the same procedure as described above for
the preparation of (S,S,S,S)-11a, the reaction of (S,S,S,S)-10a with bis(4-
tert-butylphenyl)phosphine oxide afforded (S,S,S,S)-11c as an amorphous
white solid (92% yield). [a]2D0 =À69.0 (c=1.01 in CHCl3); 1H N MR
(300 MHz, CDCl3, TMS): d=0.87 (t, J=11.9 Hz, 6H), 1.32 (s, 36H), 2.99
(d, J=7.3 Hz, 2H), 3.71 (m, 4H), 5.40 (d, J=7.3 Hz, 2H), 7.03–7.68 (m,
CHCl3); 1H NMR (300 MHz, CDCl3, TMS): d=0.86 (t, J=7.1 Hz, 6H),
3.85 (q, J=7.1 Hz, 4H), 3.93 (d, J=4.4 Hz, 2H), 4.92 (d, J=4.4 Hz, 2H),
7.20–7.40 (m, 8H) ppm; 19F NMR (282 MHz, CDCl3): d=À74.4 ppm; 13C
NMR (75 MHz, CDCl3): d=170.82, 147.75, 130.62, 129.18, 128.55, 128.44,
121.11, 120.67, 116.43, 60.80, 43.79, 38.01, 13.61 ppm; EI-MS (70 eV): m/z
(%): 127 (38), 147 (54), 175 (100), 181 (45), 210 (98), 501 (39), 574
([M]+, 30); IR (KBr): n=2980, 1728, 1708, 1492, 1454, 1420, 1404, 1373,
1343, 1319, 1250, 1226, 1204, 1142, 1076, 1047, 1035, 941, 894, 876, 826,
786, 771, 743, 729, 620, 607, 573, 520, 481 cmÀ1; elemental analysis calcd
(%) for C24H22O10F6S2: C 44.44, H 3.42; found; C 44.47, H 3.45.
24H) ppm; 31P NMR (121.46 MHz, CDCl3): d=12.6 ppm; 13C
N MR
(75 MHz, CDCl3): d=171.22, 154.87, 154.83, 154.79, 142.62, 142.51,
133.17, 133.10, 133.00, 132.09, 131.96, 131.88, 131.74, 130.37, 130.29,
129.30, 129.17, 129.00, 128.89, 126.19, 126.02, 125.44, 125.30, 125.28, 59.90,
44.54, 42.39, 42.31, 34.91, 31.13, 31.09, 29.64, 13.93 ppm; IR (KBr): n=
3439, 3062, 2964, 2928, 2870, 1726, 1599, 1498, 1465, 1444, 1394, 1366,
1308, 1264, 1189, 1137, 1114, 1093, 1038, 1018, 829, 802, 751, 613, 592,
567, 520, 490 cmÀ1; EI-MS (70 eV): m/z (%): 313 (53), 415 (59), 653 (40),
663 (78), 804 (64), 903 (96), 904 (100), 976 (23), 903 (96); HRMS (EI):
calcd for C62H74O6P2 [M+ÀCOOEt]: 903.4671; found: 903.4665.
(À)-(S,S,S,S)-11d: Following the same procedure as described above for
the preparation of (S,S,S,S)-11a, the reaction of (S,S,S,S)-10a with di(3-
tolyl)phosphine oxide afforded (S,S,S,S)-11d as an amorphous white solid
(97% yield). [a]2D0 =À80.8 (c=1.01 in CHCl3); 1H NMR (300 MHz,
CDCl3, TMS): d=0.86 (t, J=6.7 Hz, 6H), 2.34 (s, 3H), 2.38 (s, 3H), 2.96
(d, J=8.6 Hz, 2H), 3.73 (q, J=8.4 Hz, 4H), 5.33 (d, J=8.5 Hz, 2H),
6.98–7.66 (m, 24H) ppm; 31P NMR (121.46 MHz, CDCl3): d=12.7 ppm;
13C NMR (75 MHz, CDCl3): d=170.74, 142.17, 142.06, 138.08, 138.05,
137.92, 137.90, 133.05, 132.84, 132.67, 132.41, 132.29, 132.19, 132.11,
132.06, 131.81, 131.698, 131.49, 129.09, 129.04, 128.96, 128.91, 128.77,
128.07, 127.93, 127.90, 126.00, 125.83, 59.61, 44.62, 42.18, 42.10, 21.13,
13.67 ppm; IR (KBr): n=2980, 1722, 1592, 1477, 1444, 1370, 1307, 1222,
1174, 1114, 1036, 871, 785, 697, 559, 464 cmÀ1; EI-MS (70 eV): m/z (%):
229 (58), 331 (49), 580 (56), 690 (51), 734 (59), 735 (96), 736 (100), 737
(36), 808 (18); HRMS (EI): calcd for C50H50O6P2 [M+]: 808.3083; found:
808.3076.
(À)-(S,S,S,S)-10b: Following the same procedure as described above for
the preparation of (S,S,S,S)-10a, the reaction of (S,S,S,S)-9b with Tf2O af-
forded (S,S,S,S)-10b as a white solid (99% yield). M.p. 54–568C; [a]D20
=
1
À74.6 (c=0.99 in CHCl3); H NMR (300 MHz, CDCl3, TMS): d=3.37 (s,
6H), 3.98 (d, J=9.0 Hz, 2H), 4.93 (d, J=9.0 Hz, 2H), 6.26–7.38
(m, 8H) ppm; 19F NMR (282 MHz, CDCl3): d=À74.5 ppm; 13C N MR
(75 MHz, CDCl3): d=171.26, 147.66, 130.40, 129.25, 128.43, 128.38,
121.03, 120.64, 116.41, 51.69, 43.83, 37.97 ppm; IR (KBr): n=1734,
1489, 1452, 1423, 1406, 1338, 1290, 1251, 1218, 1162, 1139, 1078,
908, 861, 817, 769, 745, 648, 628, 603 cmÀ1
H]: 621.3.
;
ESI-MS [M+
(À)-(S,S,S,S)-10c: Following the same procedure as described above for
the preparation of (S,S,S,S)-10a, the reaction of (S,S,S,S)-9c with Tf2O af-
forded (S,S,S,S)-10c as a white solid (95% yield). [a]2D0 =À28.1 (c=1.25
in CHCl3); 1H NMR (CDCl3, 300 MHz, TMS): d=4.02 (d, J=8.7 Hz,
2H), 4.76 (d, J=12.3 Hz, 2H), 4.86 (d, J=12.3 Hz, 2H), 4.92 (d, J=
8.7 Hz, 2H), 7.05–7.27 (m, 18H) ppm; 19F NMR (282 MHz, CDCl3): d=
À74.3 ppm; 13C NMR (75 MHz, CDCl3): d=171.26, 147.66, 130.40,
129.25, 128.43, 128.38, 121.03, 120.64, 116.41, 51.69, 43.83, 37.97 ppm; IR
(KBr): n=1729, 1490, 1453, 1421, 1404, 1382, 1332, 1250, 1216, 1139,
1078, 904, 863, 769, 697, 605 cmÀ1; ESI-MS [M++Na]: 731.1; HRMS
(FT): calcd for C34H26O10NaF6 [M++Na]: 731.1322; found: 731.1317.
(À)-(S,S,S,S)-11e: Following the same procedure as described above for
the preparation of (S,S,S,S)-11a, the reaction of (S,S,S,S)-10a with di(3,5-
xylyl)phosphine oxide afforded (S,S,S,S)-11e as an amorphous white solid
(95% yield). [a]2D0 =À99.4 (c=1.00 in CHCl3); 1H NMR (300 MHz,
CDCl3, TMS): d=0.86 (t, J=7.3 Hz, 6H), 2.29 (s, 12H), 2.32 (s, 12H),
2.93 (d, J=4.3 Hz, 2H), 3.75 (q, J=6.7 Hz, 4H), 5.24 (d, J=4.3 Hz, 2H),
7.00–7.40 (m, 20H) ppm; 31P NMR (121.46 MHz, CDCl3): d=31.0 ppm;
(À)-(S,S,S,S)-11a: DMSO (6 mL) and diisopropylethylamine (1.8 mL,
10.0 mmol) were added to a mixture of (S,S,S,S)-10a (0.648 g, 1.0 mmol),
diphenylphosphine oxide (0.808 g, 4.0 mmol), Pd(OAc)2 (24.0 mg,
0.10 mmol), and dppp (74.8 mg, 0.15 mmol) and the mixture was stirred
at 1008C for 12 h. After cooling to room temperature, the reaction mix-
ture was diluted with ethyl acetate, washed with water twice and then
Chem. Eur. J. 2004, 10, 5952 – 5963
www.chemeurj.org
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5959

K. Ding et al.
FULL PAPER
13C NMR (75 MHz, CDCl3) : d=171.02, 142.36, 142.26, 138.16, 138.10,
137.99, 137.93, 133.27, 133.13, 132.98, 131.96, 131.77, 129.81, 129.76,
129.69, 129.63, 128.97, 126.19, 126.02, 59.89, 45.01, 42.46, 21.25,
13.90 ppm; IR (KBr): n=3012, 2980, 1723, 1600, 1444, 1369, 1307, 1274,
1185, 1129, 1037, 871, 850, 693, 582, 525, 423 cmÀ1; EI-MS (70 eV): m/z
(%): 257 (55), 359 (33), 360 (43), 608 (68), 746 (35), 791 (90), 792 (100),
793 (48), 864 (24); HRMS (EI): calcd for C54H58O6P2 [M+]: 864.3709;
found: 864.3733.
2980, 1722, 1605, 1586, 1509, 1477, 1464, 1435, 1369, 1328, 1303, 1266,
1216, 1159, 1134, 1093, 1070, 1035, 998, 745, 695, 546, 497, 416 cmÀ1; ele-
mental analysis calcd (%) for C46H42O4P2: C 76.65, H 5.87; found: C
76.59, H 5.93.
(À)-(S,S,S,S)-3b: Following the same procedure as described above for
the preparation of (S,S,S,S)-3a, the reduction of (S,S,S,S)-11b afforded
(S,S,S,S)-3b as an amorphous white solid (80% yield). [a]2D0 =À69.0 (c=
1
1.22 in CHCl3); H NMR (300 MHz, CDCl3, TMS): d=0.73 (t, J=7.3 Hz,
(À)-(S,S,S,S)-11 f: Following the same procedure as described above for
the preparation of (S,S,S,S)-11a, the reaction of (S,S,S,S)-10a with di(4-
tolyl)phosphine oxide afforded (S,S,S,S)-11 f as an amorphous white solid
(83% yield). [a]2D0 =À72.0 (c=1.00 in CHCl3); 1H NMR (300 MHz,
CDCl3, TMS): d=0.86 (t, J=7.3 Hz, 6H), 2.40 (s, 12H), 3.04 (d, J=
7.0 Hz, 2H), 3.73 (m, 4H), 5.38 (d, J=7.0 Hz, 2H), 6.95–7.65 (m,
6H), 3.58–3.80 (m, 18H), 5.05 (d, J=4.3 Hz, 2H), 6.63–7.25 (m,
24H) ppm; 31P NMR (121.46 MHz, CDCl3): d=À16.5 ppm; 13C N MR
(75 MHz, CDCl3): d=171.43, 160.13, 160.05, 141.18, 140.87, 138.55,
138.36, 135.85, 135.61, 135.56, 135.33, 132.00, 127.99, 127.52, 127.42,
126.83, 126.73, 126.52, 114.12, 114.01, 113.92, 59.81, 54.93, 54.88, 43.59,
42.25, 41.95, 29.46, 13.64 ppm; IR (KBr): n=3055, 2836, 1722, 1594, 1568,
1498, 1463, 1441, 1369, 1305, 1286, 1248, 1177, 1135, 1095, 1031, 827, 797,
752, 531, 501, 419 cmÀ1; ESI-MS [M++H]: 841.5; HRMS (FT): calcd for
C50H51O8P2 [M++H]: 841.3053; found: 841.3033.
24H) ppm; 31P NMR (121.46 MHz, CDCl3): d=12.7 ppm; 13C
N MR
(75 MHz, CDCl3): d=171.25, 142.57, 142.47, 141.97, 141.93, 141.87,
133.20, 133.12, 132.95, 132.25, 132.12, 131.84, 130.44, 130.30, 129.22,
129.14, 129.05, 128.90, 126.14, 125.97, 59.97, 44.81, 42.37, 42.29, 29.64,
21.59, 13.87, 0.97 ppm; IR (KBr): n=2962, 2925, 2854, 1724, 1602, 1500,
1444, 1399, 1369, 1309, 1262, 1216, 1184, 1114, 1099, 1036, 807, 756, 725,
659, 634, 620, 545, 524, 459 cmÀ1; EI-MS (70 eV): m/z (%): 91 (43), 226
(67), 229 (100), 245 (84), 331 (35), 579 (41), 688(29), 735 (66), 808 (12);
HRMS (EI): calcd for C50H50O6P2 [M+]: 808.3083; found: 808.3085.
(À)-(S,S,S,S)-3c: Following the same procedure as described above for
the preparation of (S,S,S,S)-3a, the reduction of (S,S,S,S)-11c afforded
(S,S,S,S)-3c as an amorphous white solid (91% yield). [a]2D0 =À67.8 (c=
1
0.99 in CHCl3); H NMR (300 MHz, CDCl3, TMS): d=0.75 (t, J=6.7 Hz,
6H), 1.31 (s, 18H), 1.33 (s, 18H), 3.65–3.76 (m, 4H), 3.82 (d, J=4.3 Hz,
2H), 5.18 (d, J=4.3 Hz, 2H), 6.72–7.69 (m, 24H) ppm; 31P
N MR
(121.46 MHz, CDCl3): d=À15.9 ppm; 13C NMR (75 MHz, CDCl3): d=
171.70, 151.64, 151.56, 141.85, 141.52, 138.17, 137.99, 134.25, 133.98,
133.93, 133.67, 133.27, 133.14, 132.85, 132.73, 128.26, 126.86, 126.56,
126.53, 125.51, 125.41, 125.34, 59.99, 43.84, 43.78, 42.42, 42.12, 34.63,
34.60, 31.31, 31.24, 13.83 ppm; IR (KBr): n=2964, 2904, 2869, 1725, 1600,
1510, 1494, 1463, 1393, 1365, 1331, 1305, 1268, 1142, 1094, 1084, 1037,
1016, 923, 827, 752, 592, 560 cmÀ1; ESI-MS [M++H]: 945.8; HRMS (FT)
calcd for C62H75O4P2 [M++H]: 945.5135; found: 945.5138.
(À)-(S,S,S,S)-11g: Following the same procedure as described above for
the preparation of (S,S,S,S)-11a, the reaction of (S,S,S,S)-10b with diphe-
nylphosphine oxide afforded (S,S,S,S)-11g as an amorphous white solid
(98% yield). [a]2D0 =À50.0 (c=1.06 in CHCl3); 1H NMR (300 MHz,
CDCl3, TMS): d=2.95 (d, J=9.0 Hz, 2H), 3.23 (s, 6H), 5.33 (d, J=
8.7 Hz, 2H), 6.91–7.75 (m, 28H) ppm; 31P NMR (121.46 MHz, CDCl3):
d=31.5 ppm; 13C NMR (75 MHz, CDCl3): d=171.50, 142.27, 142.18,
133.28, 133.20, 133.14, 133.02, 132.73, 132.31, 132.28, 132.22, 132.17,
132.09, 132.04, 131.91, 131.75, 131.71, 131.64, 131.60, 131.37, 128.93,
128.80, 128.54, 128.51, 128.38, 128.35, 126.39, 126.22, 51.15, 45.14, 42.39,
42.32 ppm; IR (KBr): n=1728, 1437, 1189, 1135, 1117, 1100, 751, 721,
696, 553, 514 cmÀ1; ESI-MS [M++H]: 825.2; HRMS (FT): calcd for
C44H38O6P2N a [M++Na]: 747.2036; found: 747.2044.
(À)-(S,S,S,S)-3d: Following the same procedure as described above for
the preparation of (S,S,S,S)-3a, the reduction of (S,S,S,S)-11d afforded
(S,S,S,S)-3d as an amorphous white solid (76% yield). [a]2D0 =À70.6 (c=
1
1.04 in CHCl3); H NMR (300 MHz, CDCl3, TMS): d=0.77 (t, J=6.7 Hz,
6H), 2.31 (s, 6H), 2.32 (s, 6H), 3.67–3.79 (m, 6H), 5.18 (d, J=4.3 Hz,
2H), 6.76–7.51 (m, 24H) ppm; 31P NMR (121.46 MHz, CDCl3): d=
À13.2 ppm; 13C NMR (75 MHz, CDCl3): d=171.45, 141.71, 141.38,
137.91, 137.81, 137.76, 137.65, 137.57, 137.38, 136.41, 136.26, 135.90,
135.77, 135.08, 134.77, 134.45, 132.64, 131.52, 131.28, 131.06, 130.84,
129.39, 129.41, 128.98, 128.37, 128.25, 128.14, 126.87, 126.50, 59.90, 43.87,
42.50, 42.18, 21.30, 13.65 ppm; IR (KBr): n=3422, 3056, 2980, 2925, 2870,
1721, 1592, 1489, 1477, 1444, 1405, 1370, 1332, 1307, 1246, 1219, 1174,
1136, 1114, 1036, 998, 925, 872, 784, 758, 697, 566, 559, 464 cmÀ1; ESI-MS
[M++H]: 777.5; HRMS (ESI) calcd for C50H51O4P2 [M++H]: 777.3263;
found: 777.3235.
(À)-(S,S,S,S)-11h: Following the same procedure as described above for
the preparation of (S,S,S,S)-11a, the reaction of (S,S,S,S)-10c with diphe-
nylphosphine oxide afforded a mixture of the by-product BnP(O)Ph2 and
(S,S,S,S)-11h. Isolation of the desired pure (S,S,S,S)-11h proved to be
very difficult. The mixture was directly used in subsequent reduction to
(À)-(S,S,S,S)-3h without further purification (see synthesis of (À)-
(S,S,S,S)-3h) To get an unambiguous identification of compound
(S,S,S,S)-11h, however, its pure form was obtained in quantitative yield
by oxidation of (À)-(S,S,S,S)-3h with 30% H2O2 in THF. The spectros-
copic data are as follows: [a]2D0 =À75.8 (c=1.01 in CHCl3); 1H N MR
(300 MHz, CDCl3, TMS): d=3.05 (d, J=8.7 Hz, 2H), 4.43 (d, J=8.4 Hz,
2H), 4.57 (d, J=12.3 Hz, 2H), 4.74 (d, J=12.3 Hz, 2H), 6.90–7.70 (m,
(À)-(S,S,S,S)-3e: Following the same procedure as described above for
the preparation of (S,S,S,S)-3a, the reduction of (S,S,S,S)-11e afforded
(S,S,S,S)-3e as an amorphous white solid (74% yield). [a]2D0 =À131.9 (c=
38H) ppm; 31P NMR (121.46 MHz, CDCl3): d=31.3 ppm; 13C
N MR
(75 MHz, CDCl3): d=170.11, 141.39, 141.28, 134.40, 132.22, 132.14,
132.11, 131.44, 131.27, 131.24, 131.14, 131.10, 130.73, 130.60, 128.11,
127.98, 127.55, 127.50, 127.38, 127.34, 127.21, 127.02, 125.47, 125.31, 65.37,
43.73, 41.53, 41.45, 28.67 ppm; IR (KBr): n=1723, 1438, 1306, 1262, 1186,
1
1.01 in CHCl3); H NMR (300 MHz, CDCl3, TMS): d=0.70 (t, J=6.7 Hz,
6H), 2.16 (s, 12H), 2.20 (s, 12H), 3.66 (m, 6H), 5.25 (d, J=4.2 Hz, 2H),
6.60–7.00 (m, 20H); 31P NMR (121.46 MHz, CDCl3): d=À12.5 ppm; IR
(KBr): n=3396, 2980, 2921, 2862, 1723, 1600, 1467, 1444, 1370, 1307,
1160, 1134, 1116, 1100, 1071, 1027, 752, 722, 695, 553, 513 cmÀ1; ESI-MS
1274, 1182, 1130, 1073, 1037, 872, 851, 757, 723, 693, 581, 525, 468 cmÀ1
;
+
[M++H]: 877.3; HRMS (FT): calcd for C56H46O6P2N
a
[M+Na]:
EI-MS (70 eV): m/z (%): 343 (14), 416 (8), 555 (23), 591 (100), 592 (30),
593 (9), 727 (8), 759 (10); elemental analysis calcd (%) for C54H58O4P2: C
77.86, H 7.02; found: C 77.66, H 7.18.
899.2662; found: 899.2667.
(À)-(S,S,S,S)-3a: HSiCl3 (2.85 mL, 25.0 mmol) was added to a solution of
(S,S,S,S)-11a (0.752 g, 1.0 mmol) and PhNMe2 (7.2 mL, 25.0 mmol) in
dried toluene (8 mL) at 08C. The reaction mixture was stirred for 0.5 h,
and then heated at 1008C with stirring for an additional 12 h. The reac-
tion was quenched at room temperature with concentrated aqueous
NaHCO3. The mixture was filtered through Celite, and the filtrate was
extracted with diethyl ether, washed with water and brine. The organic
phase was dried over Na2SO4, filtered and concentrated under reduced
pressure. The residue was submitted to chromatographic separation on
silica gel using hexane/EtOAc (10:1) as eluent to give an amorphous
white solid (0.53 g, 74%). [a]2D0 =À111.2 (c=1.00 in CHCl3); 1H N MR
(300 MHz, CDCl3, TMS): d=0.77 (t, J=7.2 Hz, 6H), 3.72 (m, 6H), 5.21
(d, J=3.3 Hz, 2H), 6.70–7.40 (m, 28H) ppm; 31P NMR (121.46 MHz,
CDCl3): d=À13.2 ppm; EI-MS (70 eV): m/z (%): 183 (12), 201 (19), 287
(23), 471 (11), 535 (100), 536 (26), 563 (9), 580 (9); IR (KBr): n=3053,
(À)-(S,S,S,S)-3 f: Following the same procedure as described above for
the preparation of (S,S,S,S)-3a, the reduction of (S,S,S,S)-11 f afforded
(S,S,S,S)-3 f as an amorphous white solid (76% yield). [a]2D0 =À76.4 (c=
1
0.75 in CHCl3); H NMR (300 MHz, CDCl3, TMS): d=0.79 (t, J=9.2 Hz,
6H), 2.38 (s, 6H), 2.35 (s, 6H), 3.66–3.80 (m, 6H), 5.17 (d, J=3.6 Hz,
2H), 6.71–7.29 (m, 24H) ppm; 31P NMR (121.46 MHz, CDCl3): d=
À15.2 ppm; 13C NMR (75 MHz, CDCl3): d=171.67, 141.71, 141.38,
138.56, 138.07, 137.88, 134.54, 134.27, 133.99, 133.36, 133.24, 132.76,
132.64, 132.54, 129.37, 129.28, 129.18, 128.24, 126.87, 126.71, 126.64, 60.03,
43.87, 43.82, 42.48, 42.17, 29.67, 21.34, 13.76 ppm; IR (KBr): n=2958,
2924, 2854, 1723, 1497, 1463, 1441, 1369, 1304, 1215, 1186, 1160, 1093,
1036, 806, 750, 628, 508 cmÀ1; ESI-MS [M++H]: 777.5; HRMS (FT) calcd
for C50H51O4P2 [M++H]: 777.3263; found: 777.3257.
5960
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5952 – 5963

Bisphosphine Ligands in Pd-Catalyzed Allylic Substitution Reactions
5952 – 5963
(À)-(S,S,S,S)-3g: Following the same procedure as described above for
the preparation of (S,S,S,S)-3a, the reduction of (S,S,S,S)-11g afforded
(S,S,S,S)-3g as an amorphous white solid (75% yield). [a]2D0 =À110.5 (c=
132.71, 132.34, 132.22, 128.39, 126.36, 125.57, 125.49, 63.26, 48.91, 40.78,
40.71, 40.06, 39.81, 34.63, 34.59, 33.87, 31.28, 31.19, 31.06, 25.56,
24.90 ppm; IR (KBr): n=3384, 3055, 2963, 2868, 1494, 1463, 1392, 1363,
1268, 1201, 1084, 1031, 1016, 827, 751, 591, 560 cmÀ1; EI-MS (70 eV): m/z
(%): 546 (100), 775 (80), 774 (66), 57 (62), 399 (57), 640 (51), 641 (51),
477 (50), 860 (33), 861 (30) [M++H]; HRMS (EI) calcd for C58H70O2P2
[M+]: 860.4851; found: 860.4828.
1
1.02 in CHCl3); H NMR (300 MHz, CDCl3, TMS): d=3.25 (s, 6H), 3.72
(d, J=9.0 Hz, 2H), 5.23 (d, J=7.5 Hz, 2H), 6.83–7.41 (m, 28H) ppm; 31P
NMR (121.46 MHz, CDCl3): d=À13.2 ppm; 13C NMR (75 MHz, CDCl3):
d=171.94, 141.74, 141.40, 137.14, 136.65, 136.51, 136.04, 135.90, 134.49,
134.22, 134.14, 133.87, 132.88, 128.68, 128.56, 128.47, 128.42, 128.32,
127.05, 126.54, 126.46, 51.11, 44.17, 44.11, 42.59, 42.26 ppm; IR (KBr):
n=2947, 1728, 1434, 1334, 1305, 1161, 1026, 744, 696, 498 cmÀ1; ESI-MS
[M++H]: 693.2; HRMS (FT) calcd for C44H38O4P2N a M[++Na]:
715.2138; found: 715.2168.
(À)-(S,S,S,S)-4d: AcOH (80.0 mL, 1.38 mmol) was added to a mixture of
(S,S,S,S)-4a (0.175 g, 0.276 mmol), DCC (0.285 g, 1.38 mmol) and DMAP
(0.017 g, 0.138 mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred
for 12 h and the precipitated urea was removed by filtration through
Celite. The filtrate was concentrated under reduced pressure and then
submitted to chromatographic separation on silica gel using hexane/
EtOAc (5:1) as eluent to give an amorphous white solid (0.143 g, 81%).
[a]2D0 =À65.0 (c=0.80 in CHCl3); 1H NMR (300 MHz, CDCl3, TMS): d=
1.78 (s, 6H), 2.75 (d, J=7.5 Hz, 2H), 3.85–3.88 (m, 4H), 4.71 (d, J=
7.5 Hz, 2H), 6.67–7.42 (m, 28H) ppm; 31P NMR (121.46 MHz, CDCl3):
d=À12.0 ppm; 13C NMR (75 MHz, CDCl3): d=170.92, 141.99, 141.66,
136.76, 136.59, 136.49, 136.35, 135.93, 135.79, 134.59, 134.32, 133.90,
133.649, 132.958, 128.957, 128.908, 128.751, 128.658, 128.560, 126.73,
126.64, 64.33, 40.18, 39.93, 37.41, 37.34, 20.73 ppm; IR (KBr): n=3056,
2925, 2853, 1739, 1590, 1463, 1437, 1368, 1238, 1187, 1116, 1031, 917, 748,
722, 697, 546 cmÀ1; EI-MS (70 eV): m/z (%): 536 (100), 535 (86), 537
(33), 550 (31), 549 (27), 287 (20), 472 (20), 471 (19), 720 (7) [M+];
HRMS (EI) calcd for C46H42O4P2 [M+]: 720.2509; found: 720.2534.
(À)-(S,S,S,S)-3h: Following the same procedure as described above for
the preparation of (S,S,S,S)-3a, the reduction of (S,S,S,S)-11h afforded
(S,S,S,S)-3h as an amorphous white solid (yield of the last two steps from
1
(S,S,S,S)-10c, 30%). [a]D20 =À109.0 (c=1.00 in CHCl3); H NMR (CDCl3,
300 MHz, TMS): d=3.79 (d, J=9.0 Hz, 2H), 4.57 (d, J=12.3 Hz, 2H),
4.74 (d, J=12.3 Hz, 2H), 5.22–5.25 (m, 2H), 6.72–7.38 (m, 38H); 31P
NMR (121.46 MHz, CDCl3): d=À13.4 ppm; 13C NMR (75 MHz, CDCl3):
d=171.56, 141.57, 141.24, 137.71, 137.52, 136.44, 136.29, 135.77, 135.63,
135.35, 134.58, 134.47, 134.38, 134.20, 134.11, 132.79, 128.75, 128.68,
128.61, 128.52, 128.49, 128.37, 128.26, 127.97, 127.13, 126.58, 66.42, 43.96,
42.73, 42.40 ppm; IR (KBr): n=3053, 1723, 1435, 1301, 1216, 1157, 1133,
1026, 1001, 744, 695, 499 cmÀ1; ESI-MS [M++H]: 845.3; HRMS (FT)
calcd for C56H47O4P2 [M++H]: 845.2944; found: 845.2963.
(À)-(S,S,S,S)-4a: Compound (S,S,S,S)-1a (1.07 g, 1.5 mmol) in Et2O
(À)-(S,S,S,S)-4e: Following the same procedure as described above for
the preparation of (S,S,S,S)-4d, the esterification of (S,S,S,S)-4a with ben-
zoic acid afforded (S,S,S,S)-4e as an amorphous white solid (85% yield).
[a]2D0 =À88.3 (c=0.875 in CHCl3); 1H NMR (300 MHz, CDCl3, TMS):
d=2.84–2.88 (m, 2H), 3.96 (t, J=9.0 Hz, 2H), 4.21 (t, J=9.0 Hz, 2H),
4.85 (d, J=7.0 Hz, 2H), 6.72–7.90 (m, 38H) ppm; 31P NMR (121.46 MHz,
CDCl3): d=À12.8 ppm; 13C NMR (75 MHz, CDCl3): d=166.68, 141.93,
141.61, 137.32, 137.15, 136.73, 136.59, 135.97, 135.83, 134.94, 134.67,
134.36, 134.10, 133.28, 132.97, 130.43, 129.90, 129.22, 129.18, 129.07,
128.98, 128.89, 128.79, 128.44, 127.03, 65.18, 40.31, 40.03, 38.21, 38.14,
30.41, 29.95 ppm; IR (KBr): n=2925, 2854, 1717, 1435, 1315, 1264, 1176,
1112, 1070, 1026, 804, 745, 711, 696, 545, 501 cmÀ1; ESI-MS [M++H]:
845.3; HRMS (FT) calcd for C56H47O4P2 [M++H]: 845.2944; found:
845.2938.
(20 mL) was added to
a Schlenk tube containing LiAlH4 (0.46 g,
12.0 mmol) and dried Et2O (30 mL) at 08C. The mixture was stirred for
10 min, and then the reaction was quenched with water. The precipitate
was filtered and washed with CH2Cl2 three times. The combined organic
phases were dried over Na2SO4, filtered and concentrated under reduced
pressure. The resulting amorphous white solid was recrystallized in
EtOAc to give (À)-(S,S,S,S)-4a as white crystals (0.80 g, 85%). M.p.
190.0–191.08C; [a]2D0 =À88.4 (c=0.975 in CHCl3); 1H NMR (300 MHz,
CDCl3, TMS): d=2.58 (d, J=6.3 Hz, 2H), 3.31–3.44 (m, 4H), 4.62 (d, J=
6.3 Hz, 2H), 6.67–7.41 (m, 28H) ppm; 31P NMR (121.46 MHz, CDCl3):
d=À12.7 ppm; IR (KBr): n=3360, 3047, 1584, 1432, 1066, 1032, 762, 750,
741, 695 cmÀ1; EI-MS (70 eV): m/z (%): 451 (100), 287 (92), 549 (92), 183
(90), 363 (66), 361 (55), 559 (54), 471 (42); elemental analysis calcd (%)
for C42H38O2P2: C 79.23, H 6.02; found: C 79.01, H 6.10.
(À)-(S,S,S,S)-4 f: Following the same procedure as described above for
the preparation of (S,S,S,S)-4d, the esterification of (S,S,S,S)-4c with
AcOH afforded (S,S,S,S)-4 f as an amorphous white solid (85% yield).
[a]2D0 =À90.5 (c=0.99 in CHCl3); 1H NMR (300 MHz, CDCl3, TMS): d=
1.30 (s, 18H), 1.38 (s, 18H), 1.79 (s, 6H), 2.67 (d, J=6.0 Hz, 2H), 3.80–
3.85 (m, 4H), 4.64 (d, J=6.0 Hz, 2H), 6.70–7.42 (m, 24H) ppm; 31P N MR
(121.46 MHz, CDCl3): d=À14.3 ppm; 13C NMR (75 MHz, CDCl3): d=
170.81, 151.94, 151.88, 141.72, 141.40, 137.58, 137.40, 134.40, 134.13,
133.64, 133.38, 132.90, 132.78, 132.64, 132.46, 132.35, 128.26, 126.50,
125.63, 125.54, 125.46, 64.43, 39.96, 39.71, 37.18, 37.11, 34.62, 34.58, 31.27,
31.17, 20.76 ppm; IR (KBr): n=2963, 2905, 2869, 1743, 1494, 1462, 1390,
1364, 1269, 1236, 1084, 1032, 1016, 827, 751, 582, 560 cmÀ1; ESI-MS [M+
+H]: 946.5; HRMS (FT) calcd for C62H75O4P2 [M++H]: 945.5135; found:
945.5137.
Crystal data: C42H38O2P2, formula weight 636.66, orthorhombic, space
group P212121, a=8.0449(12), b=16.257(2), c=26.605(4) Š, V=
3479.5(9) Š3, Z=4, 1calcd =1.215 gcmÀ3
,
F(000)=1344, m(MoKa)=
1.60 cmÀ1. Data collection and refinement: diffraction data were mea-
sured in the range 2qmax =2.94–56.628. A total of 7797 unique reflections
with positive intensities were recorded. The final refinement, based on
F2, converged at R=0.0490 (wR2 =0.0873) for 3284 observations having
Io >2s(Io) and R=0.1299 (wR2 =0.1053) for 7797 unique data. At conver-
À3
gence, S=0.342 and D1=À0.205 eŠ
.
(À)-(S,S,S,S)-4b: Following the same procedure as described above for
the preparation of (S,S,S,S)-4a, the reduction of (S,S,S,S)-3b afforded
(S,S,S,S)-4b as an amorphous white solid (99% yield). [a]2D0 =À47.4 (c=
0.97 in CHCl3); 1H NMR (300 MHz, CDCl3, TMS): d=1.82 (br, 2H),
2.59 (d, J=6.0 Hz, 2H), 3.34–3.39 (m, 4H), 3.79 (s, 6H), 3.83 (s, 6H),
4.53 (d, J=6.0 Hz, 2H), 6.56–7.30 (m,24H) ppm; 31P NMR (121.46 MHz,
CDCl3): d=À16.7 ppm; 13C NMR (75 MHz, CDCl3): d=160.34, 160.28,
141.97, 141.66, 138.25, 138.07, 135.97, 135.68, 135.56, 135.28, 132.36,
128.31, 127.54, 127.44, 126.67, 126.57, 126.52, 126.45, 126.36, 114.34,
114.30, 114.23, 114.19, 63.16, 55.29, 55.14, 55.10, 40.66, 40.60, 39.96, 39.71,
29.28 ppm; IR (KBr): n=2926, 1594, 1567, 1498, 1461, 1440, 1285, 1247,
MeO-PEG-O2CCH2CH2CO2H (18):[15i] NEt3 (1.40 mL, 10.0 mmol) was
added to a mixture of poly(ethylene glycol) methyl ether (MeO-PEG,
Mn =2000, 2.0 g, 1.0 mmol), succinic anhydride (0.50 g, 5.0 mmol), and
DMAP (0.122 g, 1.0 mmol) in CH2Cl2 (20 mL). The reaction mixture was
stirred for 12 h and the precipitated urea was removed by filtration
through Celite. The filtrate was concentrated under reduced pressure and
then the residue was dissolved in CH2Cl2 (2 mL). Et2O (50 mL) was
added slowly to the solution with vigorous stirring at 08C. The precipitate
formed was isolated by filtration and then dried over P2O5 in vacuo to
give the MeO-PEG derivative 18 (1.93 g, 92%). 1H NMR (300 MHz,
CDCl3, TMS): d=2.59–2.67 (m, 4H), 3.38 (s, 3H), 3.39–3.77 (polyethy-
lene glycol peaks), 4.21–4.23 (m, 2H) ppm; IR (KBr): n=2889, 2695,
1967, 1737, 1648, 1468, 1361, 1344, 1281, 1243, 1150, 1113, 1060, 964, 842,
1177, 1095, 1029, 827, 797, 747, 532 cmÀ1 ESI-MS [M++H]: 757.3;
;
HRMS (FT) calcd for C46H47O6P2 [M++H]: 757.2842; found: 757.2833.
(À)-(S,S,S,S)-4c: Following the same procedure as described above for
the preparation of (S,S,S,S)-4a, the reduction of (S,S,S,S)-3c afforded
(S,S,S,S)-4c as an amorphous white solid (95% yield). [a]2D0 =À47.6 (c=
1.02 in CHCl3); 1H NMR (300 MHz, CDCl3, TMS): d=1.32 (s, 18H),
1.36 (s, 18H), 2.57 (d, J=7.5 Hz, 2H), 3.36–3.39 (m, 4H), 4.51 (d, J=
7.5 Hz, 2H), 6.64–7.42 (m,24H) ppm; 31P NMR (121.46 MHz, CDCl3):
d=À14.9 ppm; 13C NMR (75 MHz, CDCl3): d=151.96, 151.92, 142.32,
142.00, 137.80, 137.62, 134.34, 134.07, 133.84, 133.58, 132.92, 132.81,
529 cmÀ1
.
(À)-(S,S,S,S)-5a: DCC (1.40 g, 0.63 mmol) was added to a mixture of 18
(0.125 g, 0.059 mmol), (S,S,S,S)-4a (0.20 g, 0.313 mmol) and DMAP
(0.004 g, 0.0313 mmol) in CH2Cl2 (2 mL). The reaction mixture was stir-
Chem. Eur. J. 2004, 10, 5952 – 5963
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ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5961

K. Ding et al.
FULL PAPER
red for 12 h and the precipitated urea was removed by filtration through
Celite. The filtrate was concentrated under reduced pressure and then
dissolved in CH2Cl2 (2 mL). Et2O (50 mL) was added slowly to the mix-
ture with vigorous stirring at 08C. The precipitate formed was isolated by
filtration as a white solid and purified by repeated precipitation from di-
ethyl ether as mentioned above. The solids obtained were then dried
over P2O5 in vacuo to give (À)-(S,S,S,S)-5a (0.144 g, 89%). 1H N MR
(300 MHz, CDCl3, TMS): d=2.36 (t, J=6.0 Hz, 2H), 2.50 (t, J=6.0 Hz,
2H), 2.60–2.70 (m, 2H), 3.38 (s, 3H), 3.65–3.71 (polyethylene glycol
peaks), 4.18–4.21 (m, 2H), 4.57–4.60 (m, 2H), 6.60–7.37 (m, 28H) ppm;
31P NMR (121.46 MHz, CDCl3): d=À12.391, À12.558 ppm; IR (KBr):
n=3474, 3053, 2887, 2742, 2696, 1967, 1736, 1585, 1468, 1436, 1361, 1344,
1281, 1242, 1149, 1112, 1061, 964, 843, 747, 699, 505 cmÀ1; MALDI-MS
[M++K]: 2415.4.
hexane/2-propanol (90:10) as eluent, flow rate=1.0 mLminÀ1, UV detec-
tion at l=254 nm, tR1 =9.5 min (R isomer), tR2 =12.9 min (S isomer).
Representative procedure for the allylic substitution using benzylamine
as the nucleophile: Dried CH3CN(2 mL) was added to a Schlenk flask
containing [{Pd(C3H5)Cl}2] (1.3 mg, 0.0036 mmol, 2.5 mol%) and chiral
ligand (À)-(S,S,S,S)-3 (0.009 mmol, 6.0 mol%). The mixture was stirred
at room temperature for 30 min and then 1,3-diphenylprop-2-en-1-yl ace-
tate 12 (37.8 mg, 0.15 mmol) was added. The mixture was stirred for an
additional 10 min. Benzylamine 13b (36.2 mL, 0.30 mmol) was introduced
to the reactor through a microsyringe. The reaction process was moni-
tored by TLC. After completion of the reaction, the product was purified
by flash chromatography using hexane/EtOAc (10:1) as eluent to yield
(R)-14b[6] as a colorless oil (see Table 1 for yields). 1H NMR (300 MHz,
CDCl3, TMS): d=3.75–3.81 (m, 2H), 4.43 (d, J=7.4 Hz, 1H), 6.31 (dd,
J=7.4, 15.9 Hz, 1H), 6.58 (d, J=15.9 Hz, 1H), 7.17–7.45 (m, 15H) ppm;
the enantiomeric excess was determined by HPLC on a Chiralcel OJ
column using hexane/2-propanol (93:7) as eluent, flow rate=
(À)-(S,S,S,S)-5b: Following the same procedure as described above for
the preparation of (S,S,S,S)-5a, the esterification of (S,S,S,S)-4c with 18
1
afforded (S,S,S,S)-5b as a white solid (78.6% yield). H NMR (300 MHz,
0.6 mLminÀ1, UV detection at l=254 nm, tR1 =18.8 min (S isomer), tR2
21.8 min (R isomer).
=
CDCl3, TMS): d=1.30 (s, 18H), 1.34 (s, 18H), 2.39–2.43 (m, 2H), 2.51–
2.56 (m, 2H), 2.64–2.67 (m, 2H), 3.38 (s, 3H), 3.65–3.71 (polyethylene
glycol peaks), 4.22–4.26 (m, 2H), 4.52 (d, J=7.0 Hz, 2H), 6.60–7.41 (m,
24H) ppm; 31P NMR (121.46 MHz, CDCl3): d=À14.6, À14.8 ppm; IR
(KBr): n=3447, 2949, 2887, 2742, 2696, 1967, 1735, 1700, 1653, 1599,
1559, 1467, 1394, 1361, 1344, 1281, 1242, 1149, 1114, 1060, 964, 947, 842,
756, 638, 614, 591, 562, 528 cmÀ1; MALDI-MS [M++K]: 2691.6.
(R)-Dimethyl cyclohex-2-enylmalonate (16a):[6] Compound 16a was pre-
pared in 85% yield. [a]D20 =+32.0 (c=1.21 in CH2Cl2); 87.5% ee; 1H
NMR (300 MHz, CDCl3, TMS): d=1.26–1.81 (m, 4H), 1.96–2.06 (m,
2H), 2.86–2.95 (m, 1H), 3.29 (d, J=9.6 Hz, 1H), 3.75 (s, 6H), 5.52 (dd,
J=2.3, 9.9 Hz, 1H), 5.74–5.82 (m, 1H); the enantiomeric excess was de-
termined by HPLC on a Chiralcel OB-H column using hexane/2-propa-
(À)-(S,S,S,S)-5c: AcOH (3.0 mL, 0.0516 mmol) was added to a mixture of
(S,S,S,S)-5a (0.07 g, 0.0258 mmol), DCC (0.011 g, 0.0516 mmol), and
DMAP (0.002 g, 0.013 mmol) in CH2Cl2 (1 mL). The reaction mixture
was stirred for 12 h and the precipitated urea was removed by filtration
through Celite. The filtrate was concentrated under reduced pressure and
then dissolved in CH2Cl2 (2 mL). Et2O (50 mL) was slowly added to the
mixture with vigorous stirring at 08C. The precipitate was isolated by fil-
tration as a white solid and purified by repeated precipitation from dieth-
yl ether as mentioned above. The solids obtained were then dried over
nol (90:10(, flow rate=0.8 mLminÀ1, UV detection at l=230 nm, tR1
8.3 min (R isomer), tR2 =10.8 min (S isomer).
=
(R)-N-Benzyl(cyclohex-2-enyl)amine (16b):[6] Compound 16b was pre-
pared in 74% yield. [a]D20 =+45.6 (c=0.99 in CH2Cl2); 73.2% ee; 1H
NMR (300 MHz, CDCl3, TMS): d=1.43–2.00 (m, 6H), 3.21–3.25 (m,
1H), 3.80–3.89 (m, 2H), 5.75 (m, 2H), 7.2–7.4 ppm (m, 5H); the enantio-
meric excess was determined by HPLC on a Chiralcel OB-H column
using hexane/2-propanol (95:5), flow rate=0.5 mLminÀ1, UV detection
at l=230 nm, tR1 =11.0 min (R isomer), tR2 =12.2 min (S isomer).
P2O5 in vacuo to give (À)-(S,S,S,S)-5c (0.056 g, 78.2%). 1H
N MR
General procedure for the recycling experiment with MeO-PEG-bound
ligand 5b: The reaction was performed in a glove box under a nitrogen
atmosphere. After completion of the reaction, most of the CH3CNwas
removed under reduced pressure and the residue was treated with diethyl
ether (50 mL) at À208C. The precipitated polymeric catalyst was collect-
ed by filtration and then washed with Et2O (2”10 mL). The recycled cat-
alyst was submitted to the next run of the reaction and the catalyst load-
ing was kept at 5 mol% Pd. The filtrate collected was purified by flash
chromatography in order to determine the yield and enantiomeric excess
of the reaction.
(300 MHz, CDCl3, TMS): d=1.79 (s, 3H), 2.31–2.38 (m, 2H), 2.49–2.54
(m, 2H), 2.73 (d, J=7.0 Hz, 2H), 3.38 (s, 3H), 3.65–3.71 (polyethylene
glycol peaks), 4.24 (t, J=4.8 Hz, 2H), 4.70 (d, J=7.0 Hz, 2H), 6.68–7.72
(m, 28H) ppm; 31P NMR (121.46 MHz, CDCl3): d=À12.0, À12.7 ppm;
IR (KBr): n=2887, 1738, 1627, 1467, 1436, 1361, 1344, 1281, 1242, 1149,
1112, 1060, 964, 842, 747, 698 cmÀ1; MALDI-MS [M++K]: 2457.4.
(À)-(S,S,S,S)-5d: Following the same procedure as described above for
the preparation of (S,S,S,S)-5c, the esterification of (S, S, S, S)-5b with
AcOH afforded (S,S,S,S)-5d as a white solid (73.6% yield). 1H N MR
(300 MHz, CDCl3, TMS): d=1.31 (s, 18H), 1.35 (s, 18H), 1.74–1.77 (m,
3H), 2.40–2.56 (m, 4H), 2.65–2.67 (m, 2H), 3.38 (s, 3H), 3.65–3.71 (poly-
ethylene glycol peaks), 4.22–4.26 (m, 2H), 4.50–4.52 (m, 2H), 6.00–7.68
(m, 24H) ppm; 31P NMR (121.46 MHz, CDCl3): d=À14.27, À14.73 ppm;
IR (KBr): n=3855, 3328, 2888, 2742, 1968, 1736, 1627, 1598, 1467, 1395,
1361, 1344, 1281, 1243, 1149, 1114, 1061, 964, 842, 756, 639, 613, 591, 567,
528 cmÀ1; MALDI-MS [M++K]: 2736.7.
Acknowledgements
Financial support from the National Natural Science Foundation of
China, the Chinese Academy of Sciences, the Major Basic Research De-
velopment Program of China (Grant no. G2000077506) and the Ministry
of Science and Technology of Commission of Shanghai Municipality are
gratefully acknowledged.
Representative procedure for the allylic substitution using dimethyl mal-
onate as a nucleophile: Dried CH3CN(2 mL) was added to a Schlenk
tube containing [{Pd(C3H5)Cl}2] (1.3 mg, 0.0036 mmol, 2.5 mol%) and
chiral ligand (À)-(S,S,S,S)-3 (0.009 mmol, 6.0 mol%) and the mixture was
stirred at room temperature for 30 min. Then, 1,3-diphenylprop-2-en-1-yl
acetate 12 (37.8 mg, 0.15 mmol) was added to the reactor and the mixture
was stirred for an additional 10 min. Dimethyl malonate 13a (35.2 mL,
0.30 mmol) and N,O- bis(trimethylsilyl)acetamide (78.0 mL, 0.30 mmol)
were finally added to the reaction mixture. The reaction process was
monitored by TLC and the resulting mixture was diluted with diethyl
ether (5 mL) and quenched with a saturated aqueous NH4Cl solution
(5 mL). The aqueous phase was extracted with diethyl ether (3”10 mL).
The combined organic phases were dried over Na2SO4, filtered through
Celite and concentrated under reduced pressure. The residue was submit-
ted to flash chromatography on silica gel using hexane/EtOAc (5:1) as
eluent to give the product (S)-14a[6] as a colorless oil (see Table 1 for
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Pfaltz, H. Yamamoto), Springer, Berlin, 1999; d) Lewis Acids in
Organic Synthesis (Ed.: H. Yamamoto), Wiley-VCH, New York,
2001.
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1
yields). H NMR (300 MHz, CDCl3, TMS): d=3.52 (s, 3H), 3.70 (s, 3H),
3.95 (d, J=10.8 Hz, 1H), 4.23–4.30 (m, 1H), 6.30 (dd, J=8.8, 15.8 Hz,
1H), 6.44 (d, J=15.8 Hz, 1H), 7.20–7.32 (m, 10H); the enantiomeric
excess was determined by HPLC on a Chiralpak AD column using
5962
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Chem. Eur. J. 2004, 10, 5952 – 5963

Bisphosphine Ligands in Pd-Catalyzed Allylic Substitution Reactions
5952 – 5963
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[12] CCDC-239002 contains the supplementary crystallographic data for
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Received: May 18, 2004
Published online: October 14, 2004
Chem. Eur. J. 2004, 10, 5952 – 5963
www.chemeurj.org
ꢁ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5963