Synthesis and Molecular Modeling Studies of SYNPHOS(R), a New, Efficient Diphosphane Ligand For Ruthenium-Catalyzed Asymmetric Hydrogenation

Article abstract of DOI:10.1002/ejoc.200200634

A new, optically active, atropisomeric diphosphane ligand, (2,3,2',3'-tetrahydro-5,5'-bi(1,4-benzodioxin)-6,6'-diyl)bis-(diphenylphosphane) (SYNPHOS(R)), has been synthesized, characterized, and used in ruthenium-catalyzed asymmetric hydrogenations. This new ligand has been compared with other atropisomeric diphosphanes (BINAP and MeO-BIPHEP) with respect to their dihedral angles calculated by molecular modeling and the enantioselectivity of their ruthenium-mediated hydrogenation reactions.

Full text of DOI:10.1002/ejoc.200200634

FULL PAPER
Synthesis and Molecular Modeling Studies of SYNPHOS, a New, Efficient
Diphosphane Ligand For Ruthenium-Catalyzed Asymmetric Hydrogenation
[a]
[a]
[a]
´
´
Sebastien Duprat de Paule, Severine Jeulin, Virginie Ratovelomanana-Vidal,*
[a]
[b]
[b]
ˆ
Jean-Pierre Genet,* Nicolas Champion, and Philippe Dellis
Keywords: Asymmetric catalysis / Atropisomerism / Hydrogenation / Molecular modeling / Phosphanes / Ruthenium
A new, optically active, atropisomeric diphosphane ligand,
PHEP) with respect to their dihedral angles calculated by
molecular modeling and the enantioselectivity of their ruthe-
(2,3,2Ј,3Ј-tetrahydro-5,5Ј-bi(1,4-benzodioxin)-6,6Ј-diyl)bis-
(diphenylphosphane) (SYNPHOS), has been synthesized, nium-mediated hydrogenation reactions.
characterized, and used in ruthenium-catalyzed asymmetric
hydrogenations. This new ligand has been compared with
other atropisomeric diphosphanes (BINAP and MeO-BI-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
BIPHEP,[3] or SEGPHOS,[4] have high efficiencies when ap-
plied to various transition metal-catalyzed reactions,[5] in
particular for ruthenium-catalyzed hydrogenation reac-
tions.[6] Structural variations of these ligands can provide
new chiral catalysts, with dramatic effects on the enantiose-
lectivities of their catalyzed reactions. Biphenylphosphanes
containing oxygenated groups, like MeO-BIPHEP,[7]
TUNAPHOS,[8] or SEGPHOS,[9] have exhibited slightly
In the last two decades, considerable effort has been made
in the design of new ligands for the development of highly
efficient metal-catalyzed asymmetric transformations.[1]
Nevertheless, the synthesis and applications of new and ef-
fective chiral ligands remain of great importance. Atrop-
isomeric bisphosphane ligands, such as BINAP,[2] MeO-
[a]
higher enantioselectivities than BINAP. We have recently
designed functionalized BINAP-derived ligands, such as
Digm-BINAP[10a] and MeO-NAPhePHOS,[10b] and in our
continuing interest for the synthesis and use of new chiral
diphosphane ligands in asymmetric catalysis, we decided to
focus on oxygen-containing atropisomeric ligands and
study their geometric and electronic properties.
`
´
Laboratoire de Synthese Selective Organique et Produits
´
Naturels,UMR 7573, Ecole Nationale Superieure de Chimie
de Paris,
11 rue P. et M. Curie,75231 Paris Cedex 05, France
Fax: (internat.) ϩ 33-1/44071062
E-mail: genet@ext.jussieu.fr
gvidal@ext.jussieu.fr
[b]
Synkem S.A.S.,
ˆ
47 rue de Longvic 21301 Chenove Cedex, France
Eur. J. Org. Chem. 2003, 1931Ϫ1941
DOI: 10.1002/ejoc.200200634
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1931

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V. Ratovelomanana-Vidal, J.-P. Genet et al.
FULL PAPER
This paper reports the synthesis of enantiopure (R)- and
The first aim was to achieve ortholithiation of compound
(S)-(2,3,2Ј,3Ј-tetrahydro-5,5Ј-bi(1,4-benzodioxin)-6,6Ј-diyl)- 3. The lithiated intermediate could be oxidized by FeCl3 to
bis(diphenylphosphane) [(R)- and (S)-SYNPHOS],[11] provide bis(phosphane oxide) 5, or transformed into an io-
structural information on SYNPHOS derived from its dide derivative 4 suitable for Ullmann coupling. As outlined
crystal structure and molecular modeling, and a study of in Table 1, we tried several conditions for the difficult or-
the influence of the dihedral angle of diphosphanes on the tholithiation/oxidative coupling sequence. Best results were
enantioselectivity of ruthenium-catalyzed hydrogenation re- obtained with tBuLi at low temperature (Ϫ100 °C then Ϫ70
actions.
°C) under thermodynamically controlled conditions,[12] and
compound 5, hereafter named SYNPHOSO2, was obtained
in 50% yield by using FeCl3 as the coupling agent.
Results and Discussion
Synthesis of SYNPHOS
Table 1. Ortholithiation conditions for phosphane oxide 3
The synthesis of SYNPHOS was accomplished in a five-
step procedure starting from commercial 1,4-benzodioxane.
In the first step, 1,4-benzodioxane (1) was readily bromin-
ated in quantitative yield with N-bromosuccinimide in
DMF. 6-Bromo-1,4-benzodioxane (2) was lithiated by
lithiumϪhalogen exchange with 1.1 equivalents of n-butyl-
lithium at Ϫ78 °C in THF, then reacted with 1.1 equivalents
of ClPPh2, and finally oxidized with hydrogen peroxide to
afford phosphane oxide 3 as a pale yellow solid in high
yields, as depicted in Scheme 1.
RLi
Equiv.
Yield of 5
LDA, Ϫ78 °C, 2 h
1
1
1.1
1
1.2
3
1.1
1
1
Ϫ
Ϫ
Ϫ
LDA, Ϫ50 °C, 2 h
LiNEt2, Ϫ40 °C, 3 h
nBuLi/TMEDA, Ϫ50 °C, 2 h
sBuLi/TMEDA, Ϫ60 °C, 3 h
nBuLi, Ϫ50 °C, 2 h
degradation
25%
degradation
20%
20%
50%
sBuLi, Ϫ50 °C, 2 h
tBuLi, Ϫ50 °C, 2 h
tBuLi, Ϫ100 °C then Ϫ70 °C, 4 h
Using the optimized ortholithiation conditions (tBuLi,
Ϫ100 °C then Ϫ70 °C), we achieved the formation of iodide
4 in 75% yield by reaction of the lithiated intermediate with
I2 at Ϫ70 °C in THF. The crude iodide was directly sub-
jected to the Ullmann reaction and bis(phosphane oxide) 5
was isolated in 50% yield from compound 3.
Racemic SYNPHOSO2 was resolved with O,O-diben-
zoyltartaric acid[13] [(ϩ)- or (Ϫ)-DBTA] by fractional crys-
tallization, as depicted in Scheme 3. A solution of racemic
SYNPHOSO2 in chloroform and a solution of (Ϫ)-DBTA
in ethyl acetate were mixed at room temperature (CHCl3/
EtOAc, 1:3). After a few minutes, precipitation of a 1:1
complex of (Ϫ)-DBTA and (Ϫ)-SYNPHOSO2 was ob-
served. Treatment of the tartrate complex with aqueous
base (1  KOH) provided enantiomerically enriched (Ϫ)-
SYNPHOSO2 [ee ϭ 70%, according to HPLC (Chiralcel
OD-H column)]. Enantiomerically pure (Ϫ)-SYNPHOSO2
was obtained in 70% yield, based on the amount of (Ϫ)-
SYNPHOSO2 in racemic 5, by repeating this operation four
times. Enantiomerically enriched (ϩ)-SYNPHOSO2 was re-
covered from the mother liquor after treatment with aque-
ous base. Using a method similar to that described above,
enantiomerically pure (ϩ)-SYNPHOSO2 was obtained in
70% yield, based on the amount of (ϩ)-SYNPHOSO2 in
racemic 5, from enantiomerically enriched (ϩ)-5 by using
(ϩ)-DBTA. A better procedure was found: when racemic
SYNPHOSO2 and (ϩ)-DBTA were mixed in dichlorometh-
ane at room temperature, a 1:1 complex of (ϩ)-DBTA and
(Ϫ)-SYNPHOSO2 precipitated. Treatment of the tartrate
complex with aqueous base (1  KOH) provided enantio-
merically enriched (Ϫ)-SYNPHOSO2 (ee ϭ 91%). Enantio-
merically pure (Ϫ)-SYNPHOSO2 was obtained in 90%
yield, based on the amount of (Ϫ)-SYNPHOSO2 in racemic
Scheme 1
Dimerization of compound 3 was a key step for the syn-
thesis of SYNPHOS ligand. We proceeded in two different
manners: Ullmann-type coupling with copper and oxidative
homo-coupling with iron() chloride, as shown in
Scheme 2.
Scheme 2
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Synthesis of SYNPHOS
FULL PAPER
5, by repeating this operation one more time. Interestingly,
SYNPHOSO2 with the opposite configuration, compared
to that observed from chloroform/ethyl acetate, was ob-
tained using dichloromethane.
Figure 1. X-ray structure of [(Ϫ)-DBTA·(S)-5] (Chem3D represen-
tation, H atoms omitted for clarity)
1
ment of the H NMR spectral shifts of the palladium com-
plex formed in situ with [(ϩ)-di-µ-chlorobis{2-[(dimeth-
ylamino)methyl]phenyl-C,N}dipalladium] (Scheme 5).[14,15]
The appearance of a single set of signals confirmed the en-
antiomeric purity of the diphosphanes to be Ͼ 95%.
Scheme 3. Resolution of SYNPHOSO2
A 1:1 complex of (Ϫ)-SYNPHOSO2 and (Ϫ)-DBTA was
recrystallized from ethanol, yielding colorless needles suit-
able for X-ray analysis. The crystal consists of polymeric
chains of alternating SYNPHOSO2 and DBTA molecules
connected by hydrogen bonds (Figure 1). From the internal
comparison with (Ϫ)-DBTA, the absolute configuration of
(Ϫ)-SYNPHOSO2 is unambiguously defined to be (S). The
two benzodioxane units in SYNPHOSO2 are positioned al-
most perpendicular to one another with an angle of 84.97°
between their planes. The distance between the carboxylic
oxygen atom and the oxygen atom on the phosphorus atom
Scheme 4. Reduction of SYNPHOSO2
˚
is 2.57 A.
The final step in the synthetic route was the reduction of
bis(phosphane oxide) 5. This transformation was ac-
complished by treatment of SYNPHOSO2 with trichloro-
silane/NBu3 in refluxing xylene. In this way, (Ϫ)-(S)- and
(ϩ)-(R)-SYNPHOS were obtained after simple precipi-
tation from MeOH with high yields, as depicted in
Scheme 4. The enantiomeric purity of the product obtained
from this reaction was determined by two complementary
methods. HPLC analyses of samples of diphosphanes (Ϫ)-
(S)-6 and (ϩ)-(R)-6 oxidized with hydrogen peroxide
Scheme 5
Asymmetric Hydrogenation
Since the pioneering work of Noyori[16] and Ikariya,[17]
showed that no racemization had occurred during the re- ruthenium-catalyzed asymmetric hydrogenation, especially
duction process. The enantiomeric purity of diphosphanes with atropisomeric diphosphane ligands, has become a very
(Ϫ)-(S)-6 and (ϩ)-(R)-6 was also confirmed by the assign- convenient method for producing optically active alcohols
Eur. J. Org. Chem. 2003, 1931Ϫ1941
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V. Ratovelomanana-Vidal, J.-P. Genet et al.
FULL PAPER
and other chiral building blocks.[6] For some time now, we
have been developing an efficient and general procedure for
the screening of new ligands in ruthenium-mediated asym-
metric hydrogenation.[18]
Following our convenient in situ procedure,[19] catalysts
were prepared from commercially available [Ru(COD)(2-
methylallyl)2] and SYNPHOS ligand in acetone by ad-
dition of a methanolic solution of HBr, as detailed in
Scheme 6. After removal of the solvent in vacuo, these com-
plexes were used without further purification.
Scheme 7. Hydrogenation substrates
Scheme 6. General procedure for ruthenium-mediated asymmetric
hydrogenation reactions using SYNPHOS
ing substituted β-hydroxy esters with enantiomeric excesses
Using SYNPHOS, we investigated the hydrogenation ranging from 97%, for the aromatic compound 7e, to Ͼ
reaction of various substrates: β-keto esters, α-keto esters, 99% for aliphatic compounds 7aϪd. Ruthenium-mediated
functionalized ketones, and ethylenic compounds, as de- hydrogenation is known to give poor values of ee for
picted in Scheme 7.
fluorous substrates 7f and 7g, even at high temperature (99
Hydrogenations were carried out in a stainless steel auto- °C),[20] but SYNPHOS ligand displayed higher enantiose-
clave on a 1-mmol scale using 1 mol % of catalyst. The con- lectivities (49% and 63%, respectively) than BINAP ligand
versions were determined by H NMR spectroscopy and (23% and 44%, respectively) under the same conditions.[20]
1
the enantiomeric excesses of the products by chiral GC or Enantioselectivities for the reduction of other ketone sub-
HPLC. The results are given in Table 2.
strates also turned out to be very high. α-Hydroxy esters,
In all cases, complete conversion was obtained. The cata- resulting from the asymmetric hydrogenation of compounds
lytic system based on SYNPHOS ligand gave high enanti- 8, were obtained with enantiomeric purities of 92Ϫ94% un-
omeric excesses for the reduction of β-keto esters (7aϪe) der 20 bar of hydrogen at 50 °C, except for thienyl com-
under 4 bar of hydrogen at 50 °C, providing the correspond- pound 8c, which gave a moderate 71% ee, under 10 bar
Table 2. Hydrogenation results
Substrate[a]
Ligand configuration
Solvent
pH2 [bar]
T [°C]
t [h]
ee[b] (config.)
7a
7b
7c
7d
7e
7f
7g
8a
8b
8c
9a
9b
9c
9d
10a
10b
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(R)
(R)
(S)
(R)
(R)
(R)
(S)
(S)
MeOH
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
EtOH
MeOH
MeOH
EtOH
MeOH
MeOH
MeOH
4
4
4
50
50
50
50
80
99
99
50
50
80
65
30
50
30
50
50
24
24
24
24
24
1
Ͼ 99% (R)
Ͼ 99% (R)
Ͼ 99% (R)
Ͼ 99% (R)
97% (S)
49% (R)
63% (R)
94% (S)
92% (R)
71% (R)
97% (S)
4
10
10
10
20
20
10
30
30
20
20
5
3
24
24
24
7
24
24
72
24
24
98% (R)
Ͼ 99% (S)
Ͼ 99% (R, R), de Ͼ 99%
86% (S)
2
91% (S)
[a]
1
[b]
All conversions were 100%, according to H NMR spectroscopy. See Exp. Sect. for method of ee determination.
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Synthesis of SYNPHOS
FULL PAPER
of hydrogen at 80 °C. Various functionalized ketones, like
hydroxyacetone 9a, thioketone 9b, β-keto phosphonate 9c,
and 1,3-diketone 9d, were also hydrogenated with values of
ee greater than 97%. Finally, asymmetric hydrogenation of
ethylenic substrates were satisfactory [i.e., 86% ee for methyl
(Z)-2-N-acetamidocinnamate (10a) and 91% ee for dimethyl
itaconate (10b)].
Interestingly, these complexes were also efficient using a
substrate:catalyst ratio of up to 10000 under 20 bar of
hydrogen at 50 °C, providing pure methyl (3R)-hydroxy-
butanoate on a multigram scale,[21] as shown in Scheme 8.
Scheme 8
Molecular Modeling
In addition to the crystal structure of the SYNPHOSO2/
DBTA complex, structural information about SYNPHOS
and other atropisomeric diphosphanes was obtained from
a molecular modeling study. We minimized the structures
of several complexes by CAChe MM2 calculations. We
selected [(diphosphane)PdCl2] (Figure 2) and [(diphos-
phane)RuHCl(substrate)] (Figure 3) as model complexes for
our study.
Figure 2. [(S)-SYNPHOS]PdCl2 complex (CAChe MM2 rep-
resentation)
In the palladium complex, two of the phenyl rings have
a pseudo-axial orientation and apparent areneϪarene inter- that previously reported for X-ray crystal structures of
actions with the parallel benzodioxane moiety. The other such complexes.[22]
two phenyl units have a pseudo-equatorial orientation.
The ruthenium model in Figure 3 represents an inter-
Most geometrical information in this model is similar to mediate complex formed between RuHCl[(S)-SYNPHOS]
Figure 3. Diastereomeric intermediates {[(S)-SYNPHOS]RuHCl·CH3COCH2COOCH3} (CAChe MM2 representation)
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V. Ratovelomanana-Vidal, J.-P. Genet et al.
FULL PAPER
and methyl acetoacetate, in which the β-keto ester substrate gle (θ) corresponding to the axially chiral biphenyl moiety
is chelated to the ruthenium center through the two car- (Figure 4), in a preliminary study of the steric effects of the
bonyl functions. Very recently, ruthenium(alkoxide) inter- ligands on catalyst reactivities.
mediates have been identified as catalytic species in ru-
thenium-mediated asymmetric ketone hydrogenation.[23]
Thus, we tried to represent the hydrogenation transition
state by creating a weak bond between the hydrogen atom
of the Ru-monohydride complex and the carbon atom of
the ketone moiety in the substrate. As observed in the pal-
ladium complex, the phenyl rings adopt a pseudo-axial/
equatorial orientations. There are two possible diastereoiso-
meric transition states for this complex, depending on the
orientation of the substrate (coordination of the re or si face
of the keto group).
Having evaluated the dihedral angle (θ), we decided to
compare the geometric properties of two atropisomeric di-
phosphane ligands, BINAP and MeO-BIPHEP, with
SYNPHOS. We have determined the dihedral angles in
their corresponding minimized structures. The results are
shown in Table 3.
In all the calculated structures — i.e., the free diphos-
phane, the palladium complex, and the two states of the
ruthenium complex — the dihedral angles decrease in the
following order: BINAP, MeO-BIPHEP, and SYNPHOS.
These results are in agreement with those obtained by Saito
on the minimized structures of Ikariya-type ruthenium
complexes with BINAP and MeO-BIPHEP ligands
([NH2Et2]ϩ[{RuCl(BINAP)}2(µ-Cl)3]Ϫ).[9]
It is well established that steric properties influence the
selectivities in transition metal-catalyzed reactions dramati-
cally.[8,9,24] We were interested in evaluating the dihedral an-
We then determined the relative energies of the models
of the intermediates in the ruthenium-mediated hydrogen-
ations. The results are shown in Table 4. For each ligand,
the difference in energy is around 2 kcal/mol and State 1
always has the lowest energy.[25] State 1 can be defined as
the favored transition state in this reaction.
With the (S)-configured ligands, which hinder the upper-
right and bottom-left space sections in the chiral array of
Figure 4. Dihedral angle
Table 3. Dihedral angles of minimized structures
Ligand
Dihedral angle (°)
Diphosphane
Palladium complex
Ruthenium complex
State 2
State 1
79.5
75.7
BINAP
86.2
72.3
70.7
79.1
75.1
70.2
78.1
75.3
73.2
MeO-BIPHEP
SYNPHOS
75.4
Figure 5. Quadrants diagram for (S)-SYNPHOS
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Synthesis of SYNPHOS
FULL PAPER
Correlation between Molecular Modeling and
Enantioselectivities
Table 4. Relative energies of the diastereoisomeric intermediates
[[(S)-SYNPHOS]RuHCl·CH3COCH2COOCH3]
For several years now, chemists at Hoffmann-La Ro-
che[26] and in our group[20,27] have found that MeO-BI-
PHEP ligand is sometimes more efficient than BINAP li-
gand in the ruthenium-mediated asymmetric hydrogenation
of functionalized prochiral ketones. Having in hand molec-
ular modeling information about three atropisomeric di-
Ligand
Relative energy (kcal/mol)
State 1
Ϫ51.87
Ϫ29.27
Ϫ27.55
State 2
Ϫ49.40
Ϫ27.20
Ϫ23.12
BINAP
MeO-BIPHEP
SYNPHOS
phosphane
ligands,
BINAP,
MeO-BIPHEP, and
SYNPHOS, we decided to determine the influence that
the dihedral angles have on the enantioselectivities of the
asymmetric hydrogenations of several substrates. The re-
sults are shown in Figure 6. Several substrates were hydro-
genated under strictly the same conditions for each of the
three ligands. We were pleased to see that the highest values
of ee were always obtained with SYNPHOS ligand, which
has the lowest dihedral angle.
the ruthenium complex (Figure 5), coordination of the si
face of the keto group affords the sterically less-hindered
intermediate. The modeling results are in agreement with
the stereochemical model of the quadrants diagram devel-
oped for the reduction of carbonyl derivatives with
rutheniumϪarylphosphane catalysts,[6a] as depicted in
Scheme 9.
As illustrated in Figure 7, the smaller the dihedral angle,
the higher the interaction between the bulky equatorial phe-
nyl group and the R group of the substrate. Thereby, the
enantioselectivity is enhanced, thanks to this higher chiral
differentiation.
Conclusions
We have reported here the synthesis of SYNPHOS,[28]
a new, atropisomeric, chiral diphosphane ligand, and its use
in ruthenium-catalyzed asymmetric hydrogenations. Thanks
to this efficient transition metal-catalyzed reaction, we have
access to a wide range of chiral building blocks, such as
optically active alcohols, with values of ee of up to 99%.
We have also studied the influence of the steric properties
Scheme 9. Sense of enantioselectivity in the asymmetric Ru-cata-
lyzed hydrogenation of β-keto esters
Figure 6. Correlation between θ and ee in the asymmetric ruthenium-mediated hydrogenation
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V. Ratovelomanana-Vidal, J.-P. Genet et al.
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90:10. All reactions were carried out under an atmosphere of argon
unless otherwise noted.
6-Bromo-2,3-dihydro-1,4-benzodioxine (2): 2,3-Dihydro-1,4-benzo-
dioxine (35 g, 0.257 mol) and 200 mL of anhydrous DMF were
mixed at 0 °C. N-Bromosuccinimide (54.9 g, 0.308 mmol) was ad-
ded in portions at 0 °C. After stirring for 24 h at room temperature,
the solution was concentrated in vacuo. The residue was filtered
and the precipitate was washed with CH2Cl2 (50 mL). The resulting
filtrate was treated with 30% aqueous Na2SO3 solution (50 mL),
washed with brine, and dried over MgSO4. After evaporation and
distillation (b.p. ϭ 99 °C, 0.4 Torr), compound 2 was obtained as
1
a colorless oil (54 g, quantitative). H NMR (CDCl3): δ ϭ 4.25 (s,
4 H), 6.74 (d, J ϭ 8.5 Hz, 1 H), 6.93 (dd, J ϭ 8.5, 2.3 Hz, 1 H),
7.02 (d, J ϭ 2.3 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 64.1, 112.7,
118.5, 120.1, 124.1, 142.8, 144.2 ppm. MS: m/z ϭ 214.
Figure 7. Steric hindrance and dihedral angles
(2,3-Dihydro-1,4-benzodioxin-6-yl)diphenylphosphane Oxide (3):
nBuLi (25.6 mL, 2.2  solution in hexane, 56.3 mmol) was added
dropwise to a solution of 6-bromo-2,3-dihydro-1,4-benzodioxine 2
(11 g, 51.1 mmol) in dry THF (30 mL) at Ϫ78 °C over 10 min. The
resulting suspension was stirred for an additional 1 h at Ϫ78 °C,
and then freshly distilled Ph2PCl (10.4 mL, 56.3 mmol) was added
dropwise at such a rate that the reaction temperature did not exceed
Ϫ60 °C. The orange solution was warmed to 0 °C within 2 h, dur-
ing which time the solution turned red, then yellow, and then
quenched with saturated aqueous NH4Cl (20 mL). The organic
layer was separated, washed with brine, dried over MgSO4, filtered,
and the solvents were evaporated. The solid residue was washed
with hot hexane and a light-yellow solid was collected by filtration.
This solid was suspended in MeOH (60 mL) and 30% aqueous
H2O2 (8 mL) was added dropwise at 0 °C. After stirring for 1 h at
room temperature, the resulting clear solution was treated with 30%
aqueous Na2SO3 (14 mL), stirred for an additional 1 h, and then
treated with 1  aqueous HCl (9 mL). The resulting mixture was
concentrated in vacuo to remove MeOH and the aqueous residue
was extracted with CH2Cl2 (50 mL). The organic layer was dried
over MgSO4, filtered, and the solvents were evaporated. The yellow
oily residue crystallized on standing and the solids were washed
with hot hexane to yield 3 as a white solid (15.5 g, 90%). M.p.
of the diphosphanes chelated to the ruthenium catalysts.
With CAChe MM2 calculations, we have evaluated a rep-
resentative factor of atropisomeric diphosphanes (i.e., the
dihedral angle corresponding to the axial chirality of the
biphenyl moiety). This steric parameter plays a crucial role
in the enantiofacial recognition, which exerts a dramatic ef-
fect on the enantioselectivities of ruthenium-mediated
asymmetric hydrogenation reactions: a narrower dihedral
angle provides a higher chiral differentiation. We compared
three atropisomeric diphosphane ligands that were expected
to have similar electronic properties. Evaluation of the elec-
tronic properties of these ligands and the design of new
atropisomeric diphosphanes with similar geometric proper-
ties, but with strongly different electronic properties, are
currently in progress. Such developments should assist in
the discovery of new atropisomeric diphosphane ligands
and an understanding of their steric and electronic proper-
ties, which will be published in due course.
1
150Ϫ155 °C. H NMR (CDCl3): δ ϭ 4.26 (m, 4 H), 6.95 (dd, J ϭ
11.8, 3.1 Hz, 1 H), 7.09Ϫ7.18 (m, 2 H), 7.42Ϫ7.54 (m, 6 H),
7.61Ϫ7.72 (m, 4 H) ppm. 13C NMR (CDCl3): δ ϭ 64.1, 64.4, 117.6
(d, J ϭ 14.6 Hz), 121.2 (d, J ϭ 12.1 Hz), 125.5 (d, J ϭ 10.3 Hz),
128.2, 128.4, 131.7, 131.8, 132.0, 133.6, 143.3, 146.7 ppm. 31P
NMR (CDCl3): δ ϭ 30.10 ppm. MS: m/z ϭ 335.
Experimental Section
General Remarks: 1H NMR spectra were recorded on a Bruker AC
200 at 200 MHz or on an Avance 400 at 400 MHz, 13C NMR spec-
tra were recorded on a Bruker AC 200 at 50 MHz, and 31P NMR
spectra were recorded on an Avance 400 at 162 MHz. Chemical
shifts (δ) are reported in ppm downfield relative to internal Me4Si
or external H3PO4. Coupling constants (J) are reported in Hz and
refer to apparent peak multiplicities. Mass spectra were determined
on a Ribermag instrument. Ionization was obtained either by elec-
tronic impact (EI) or chemical ionization with ammonia (DCI/
NH3), or by electrospray (ESI) for compounds (Ϫ)-(S)-6 and (ϩ)-
(R)-6. Optical rotations were measured on a PerkinϪElmer 241
polarimeter at 589 nm (sodium lamp). Melting points (m.p.) were
determined on a Kofler melting point apparatus. Gas chromato-
graphic analyses were performed on a HewlettϪPackard 5890 serie
II instrument, connected to a Merck -2500 or -2000 integrator,
using a flame-ionization detector; enantiomeric excesses were deter-
mined on chiral capillary columns: Lipodex A, Hydrodex-β-6-
TBDM, Chirasil-Val, or Megadex 5. HPLC analyses of compound
5 were conducted with a Waters 600 system, using a Daicel Chiral-
(5-Iodo-2,3-dihydro-1,4-benzodioxin-6-yl)diphenylphosphane Oxide
(4): tBuLi (2 mL, 1.5  solution in pentane, 3 mmol) was added
dropwise to a solution of 3 (1 g, 2.9 mmol) in dry THF (25 mL) at
Ϫ100 °C. Over a period of 30 min, the reaction temperature was
warmed to Ϫ70 °C, and the resulting red solution was stirred for
an additional 3 h at this temperature. I2 was then added at Ϫ70 °C
and a beige precipitate was formed. The reaction temperature was
raised to 0 °C over 2 h, during which time the mixture became a
clear red solution. This solution was treated with 20% aqueous
Na2SO3 (5 mL). The organic layer was washed with brine, dried
over MgSO4, filtered, and then the solvents were evaporated to
yield crude 4 as a yellow solid (1.34 g, containing 25% of starting
material). 1H NMR (CDCl3): δ ϭ 4.31 (m, 4 H), 6.69 (dd, J ϭ
12.7, 8.7 Hz, 1 H), 7.81 (dd, J ϭ 8.6, 2.8 Hz, 1 H), 7.47Ϫ7.58 (m,
6 H), 7.63Ϫ7.77 (m, 4 H) ppm. 31P NMR (CDCl3): δ ϭ 34.42 ppm.
MS: m/z ϭ 462.
[2,3,2Ј,3Ј-Tetrahydro-5,5Ј-bi(1,4-benzodioxin)-6,6Ј-diyl]bis-
cel chiral stationary-phase column: OD-H hexane/2-propanol, (diphenylphosphane Oxide), SYNPHOSO2 (5). Method
A
1938  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2003, 1931Ϫ1941

Synthesis of SYNPHOS
FULL PAPER
(Oxidative Coupling): tBuLi (65 mL, 1.5  solution in pentane,
90 mmol) was added dropwise to a solution of 3 (30 g, 87 mmol)
in dry THF (600 mL) at Ϫ100 °C. Over a period of 30 min, the
reaction temperature was raised to Ϫ70 °C, and the resulting red
solution was stirred for an additional 3 h at this temperature. Anhy-
drous FeCl3 (19.8 g, 122 mmol) was then added in one portion un-
der a flow of argon at Ϫ70 °C. The reaction temperature was raised
quickly to 10 °C and the brown mixture was stirred overnight at
room temperature. The solution was concentrated in vacuo, and
the brown residue was diluted with CH2Cl2 (500 mL) and treated
with 1  aqueous NaOH (50 mL). After stirring for 30 min, the
resulting suspension was filtered through celite and the filter cake
was washed with CH2Cl2 (100 mL). The organic layer was washed
with water, brine, dried over MgSO4, filtered, and the solvents were
evaporated. The resulting brown solid, containing 50% of starting
material 3, was dissolved in CHCl3 (150 mL) and a solution of
racemic dibenzoyltartaric acid (15.8 g, 44 mmol) in EtOAc
(180 mL) was added. In a few minutes, a precipitate was formed.
After filtration (the filtrate was concentrated in vacuo to give un-
changed started material 3 (15 g, 50%) as a pale yellow solid), the
solids were suspended in CH2Cl2 (200 mL) and treated with 1 
aqueous KOH (100 mL). After stirring for 30 min, the clear organic
layer was separated, washed with water, brine, dried over MgSO4,
filtered, and then the solvents were evaporated to afford pure 5
(15 g, 50%) as a white solid. M.p. Ͼ 260 °C. 1H NMR (CDCl3):
δ ϭ 3.42 (m, 2 H), 3.70 (m, 2 H), 3.92 (m, 2 H), 4.06 (m, 2 H),
6.64 (dd, J ϭ 13.3, 8.5 Hz, 2 H), 6.77 (dd, J ϭ 8.5, 3.1 Hz, 2 H),
7.26Ϫ7.31 (m, 4 H), 7.35Ϫ7.55 (m, 12 H), 7.65Ϫ7.70 (m, 4 H)
ppm. 13C NMR (CDCl3): δ ϭ 63.3, 63.9, 115.9 (d, J ϭ 14.6 Hz),
121.2, 124.5, 127.7, 127.9, 130.8, 132.1, 132.2, 132.4, 135.5, 141.0,
145.8 ppm. 31P NMR (CDCl3): δ ϭ 30.97 ppm. MS: m/z ϭ 670.
HRMS: calcd. for C40H32O6P2 [M ϩ H] 671.1752; found 671.1755.
operation was repeated as above and finally (ϩ)-(R)-5 (3.5 g, 70%
based on theory, ee Ͼ 99.9% according to HPLC) was obtained as
a white solid. [α]D ϭ ϩ143 (c ϭ 1, CHCl3). All other analytical
data were identical to those of compound 5.
Method B: A solution of rac-SYNPHOSO2 5 (26.15 g, 39 mmol)
and (Ϫ)-O,O-dibenzoyltartaric acid (14.76 g, 39 mmol) in CH2Cl2
(500 mL) was stirred at room temperature and a white precipitate
formed within a few minutes. The solids were filtered (the filtrate
was stored for the recovery of the other enantiomer) and an aliquot
of the resulting white solid was suspended in CH2Cl2 (2 mL) and
treated with 1  aqueous KOH (1 mL). After stirring for 30 min,
the clear organic layer was separated, washed with water, brine,
dried over MgSO4, filtered, and the solvents were evaporated to
afford a white solid (ee ϭ 91% (ϩ)-(R), according to HPLC). The
solids were suspended once again in CH2Cl2 (200 mL), the mixture
was filtered (the filtrate was stored for the recovery of the other
enantiomer). The resulting white solid (18.7 g, 17.8 mmol) was sus-
pended in CH2Cl2 (200 mL) and treated with 1  aqueous KOH
(100 mL). After stirring for 30 min, the clear organic layer was
separated, washed with water, brine, dried over MgSO4, filtered,
and the solvents were evaporated to afford enantiopure (ϩ)-(R)-5
(11.9 g, 91% based on theory, ee Ͼ 99.9% according to HPLC) as
a white solid. [α]D ϭ ϩ143 (c ϭ 1, CHCl3). All other analytical
data were identical to those of compound 5.
The combined filtrates were concentrated under vacuum and
treated as described above (1  KOH and usual workup). The re-
sulting white solid (14.2 g, 21.2 mmol) was then treated, in the same
manner, with (D)-(ϩ)-dibenzoyltartaric acid (8.00 g, 21.2 mmol)
and finally (Ϫ)-(S)-5 (11.6 g, 89% based on theory, ee Ͼ 99.9%
according to HPLC) was obtained as a white solid. [α]D ϭ Ϫ143
(c ϭ 1, CHCl3). All other analytical data were identical to those of
compound 5.
Method B (Ullmann-Type Coupling): A mixture of crude 4 (1.3 g,
containing 25% of 3, 2.1 mmol) and activated copper (540 mg,
8.4 mmol) in anhydrous DMF (10 mL) was heated at 140 °C for
4 h. The solvent was evaporated and the residue was treated for
5 min with hot CH2Cl2 (10 mL). The solids were filtered and
washed with CH2Cl2 (10 mL). The filtrate was washed with a satu-
rated aqueous NH4Cl solution (5 mL), dried over MgSO4, and con-
centrated. The solid residue was purified by silica gel chromatogra-
phy (CH2Cl2/MeOH, 98:2) and a white solid was obtained (500 mg,
70% based on the amount of 4). All analytical data were identical
to those of compound 5.
[2,3,2Ј,3Ј-Tetrahydro-5,5Ј-bi(1,4-benzodioxin)-6,6Ј-diyl]bis-
(diphenylphosphane), SYNPHOS (6): Tributylamine (4.24 mL,
17.90 mmol) and trichlorosilane (1.56 mL, 14.80 mmol) were added
to a suspension of 5 (1 g, 1.48 mmol) in dry xylene (10 mL). The
resulting mixture was heated at 140 °C overnight. After cooling to
room temperature, degassed 4  aqueous NaOH (10 mL) was ad-
ded dropwise and the mixture was stirred for 30 min. Dry CH2Cl2
(30 mL) was added, the organic layer was washed with degassed
distilled water (10 mL) and degassed brine (10 mL), and then con-
centrated in vacuo. MeOH (20 mL) was added and a white precipi-
tate formed. The solids were filtered under argon and dried in va-
cuo for 3 h to afford SYNPHOS 6 (860 mg, 91%) as a white solid.
Resolution of SYNPHOSO2. Method A: A solution of (Ϫ)-O,O-
dibenzoyltartaric acid (5.64 g, 14.9 mmol) in EtOAc (260 mL) was
added to
a stirred solution of rac-SYNPHOSO2 5 (10 g,
(؊)-(S)-SYNPHOS 6: M.p. Ͼ 260 °C. [α]D ϭ Ϫ44 (c ϭ 0.1,
C6H6). H NMR (CDCl3): δ ϭ 3.35 (m, 2 H), 3.83 (m, 4 H), 4.13
(m, 2 H), 6.62 (dd, J ϭ 8, 3 Hz, 2 H), 6.85 (d, J ϭ 8 Hz, 2 H),
7.05Ϫ7.10 (m, 4 H), 7.20Ϫ7.25 (m, 8 H), 7.27Ϫ7.32 (m, 8 H) ppm.
31P NMR (CDCl3): δ ϭ Ϫ14.30 ppm. MS (ESI): m/z ϭ 639.6 ([M
ϩ H]ϩ). HRMS: calcd. for C40H32O4P2 [M ϩ H] 639.1854; found
639.1844.
14.9 mmol) in CHCl3 (100 mL). After a few minutes, a precipitate
had formed. After filtration (the filtrate was stored for the recovery
of the other enantiomer), the solids were suspended in CH2Cl2
(200 mL) and treated with 1  aqueous KOH (100 mL). After stir-
ring for 30 min, the clear organic layer was separated, washed with
water, brine, dried over MgSO4, filtered, and the solvents were eva-
porated to afford enantiomerically enriched (Ϫ)-(S)-5. The oper-
ation was repeated four times and enantiomerically pure (Ϫ)-(S)-5
(ee Ͼ 99.9% according to HPLC) was obtained as a white solid
(3.5 g, 70% based on theory). M.p. Ͼ 260 °C. [α]D ϭ Ϫ142 (c ϭ 1,
CHCl3). All other analytical data were identical to those of com-
pound 5.
1
(؉)-(R)-SYNPHOS 6: M.p. Ͼ 260 °C. [α]D ϭ ϩ44 (c ϭ 0.1,
C6H6). All other analytical data were identical to those of (Ϫ)-(S)-
SYNPHOS 6.
Typical Procedure for Asymmetric Hydrogenation: (S)-SYNPHOS
(7.1 mg, 0.011 mmol) and [(COD)Ru{η3-(CH2)2CCH3}2] (3.2 mg,
0.01 mmol) were placed in a 10 mL flask, and degassed anhydrous
acetone (1 mL) was added dropwise. A methanolic solution of HBr
(122 µL, 0.18 ) was added dropwise to the suspension. The reac-
tion mixture was stirred at room temperature for about 30 min and
The combined filtrates were concentrated under vacuum and
treated as described above (1  KOH and usual workup). The re-
sulting white solid (6.2 g, 9.2 mmol) was then treated, in the same
manner, with (D)-(ϩ)-dibenzoyltartaric acid (3.5 g, 9.2 mmol). The
Eur. J. Org. Chem. 2003, 1931Ϫ1941
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1939

ˆ
V. Ratovelomanana-Vidal, J.-P. Genet et al.
FULL PAPER
an orange suspension was formed. The solvent was removed under
vacuum. The brown solid residue was used without further purifi-
cation as a catalyst for the hydrogenation reaction of the desired
substrate (1 mmol) in MeOH or EtOH (2 mL). The reaction vessel
was placed in a 500 mL stainless steel autoclave, which was pressur-
ized at the desired pressure and warmed to the desired temperature
for 24 h. The methanol was concentrated and the crude product
was passed through a short pad of silica gel (cyclohexane/EtOAc,
1:1). Conversion and ee were determined by 1H NMR spectroscopy
and chiral GC, respectively.
Acknowledgments
CNRS and SYNKEM S.A.S. are gratefully acknowledged for a
doctoral fellowship. We deeply thank Dr A. Solladie-Cavallo, from
the Department of Fine Organic Chemistry (ECPM, Strasbourg,
France), for her kind permission to use molecular modeling facili-
ties. We also thank Dr R. Schmid (Hoffmann-La Roche) for a gen-
erous gift of (S)- and (R)-MeO-BIPHEP.
´
[1]
H. B. Kagan, in Comprehensive Asymmetric Catalysis (Eds.: E.
N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer-Verlag,
X-ray Crystallographic Study: Details are listed in Table 5.
CCDC-207263 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, UK; Fax: (internat.) ϩ44Ϫ1223/336Ϫ033; E-mail:
deposit@ccdc.cam.ac.uk].
Berlin, 1999, Vol. I, Chap. 2, p. 9.
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23, 345Ϫ350.
[3]
R. Schmid, E. A. Broger, M. Cereghetti, Y. Crameri, J. For-
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R. Noyori, in Asymmetric Catalysis in Organic Synthesis,
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Table 5. Crystal data for (Ϫ)-SYNPHOSO2/(Ϫ)-DBTA
Empirical formula
Crystal class
C58H44O14P2
monoclinic
C2
24.796(4), 90
8.460(2), 117.70(2)
13.521(3), 90
2511(1)
2
2000, p. 1Ϫ110. [6d]R. Noyori, T. Ohkuma, Angew. Chem. Int.
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2002, 41, 2008Ϫ2022.
74, 77Ϫ83.
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R. Noyori, Angew. Chem. Int. Ed.
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J.-P. Genet, Pure Appl. Chem. 2002,
[6f]
Space group
˚
a (A), α (°)
[7]
[8]
[9]
˚
b (A), β (°)
˚
c (A), γ (°)
3
˚
Volume (A )
Z
Radiation
Wavelength (A)
Mo-Kα
0.710690
1.36
1026.92
1.57
T. Saito, T. Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T. Miura,
H. Kumobayashi, Adv. Synth. Catal. 2001, 343, 264Ϫ267, and
references cited therein.
˚
Density
[10] [10a]
M (g molϪ1
)
ˆ
P. Guerreiro, V. Ratovelomanana-Vidal, J.-P. Genet, P.
[10b]
µ (cmϪ1
)
Dellis, Tetrahedron Lett. 2001, 42, 3423Ϫ3426.
Michaud, M. Bulliard, L. Ricard, J.-P. Genet, A. Marinetti,
G.
ˆ
Temperature (K)
Size (mm)
Color
Shape
Diffractometer
Scan type
Reflections measured
Independent reflections
Rint.
Θmin.,max.
hmin., hmax.
kmin., kmax.
lmin., lmax.
Decay
Refinement on F
R factor
295
0.3 ϫ 0.3 ϫ 0.6
colorless
stick
EnrafϪNonius
2Θ/Ω
2418
2192
0.02
125.00
0, 29
0, 10
Chem. Eur. J. 2002, 8, 3327Ϫ3330.
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ˆ
S. Duprat de Paule, N. Champion, V. Vidal, J.-P. Genet, P.
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[13]
H. Brunner, W. Pieronczyk, B. Schönhammer, K. Streng, I.
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S. Otsuka, T. Nakamura, T. Kano, K. Tani, J. Am. Chem.
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K. Tani, L. D. Brown, J.
Ϫ16, 14
0.023
Ahmed, J. A. Ibers, M. Yokota, T. Nakamura, S. Otsuka, J.
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0.0495 R ϭ Σ||Fo| Ϫ |Fc||/Σ|Fo|
Weighted R factor
0.0645 Rw* ϭ [Σw
(||Fo| Ϫ |Fc||)2 / Σw F2o]1/2
A. Miyashita, A. Yasuda, H. Takaya, K. Toriumi, T. Ito,
[16] [16a]
3
˚
˚
∆δmin. (e/A )
Ϫ0.21
0.42
T. Souchi, R. Noyori, J. Am. Chem. Soc. 1980, 102,
3
[16b]
∆δmax. (e/A )
7932Ϫ7934.
R. Noyori, M. Ohta, Y. Hsiao, M. Kitamura,
Reflections used
σ(I) limit
Number of parameters
Goodness of fit
1839
1.50
299
1.003
J. Ohta, H. Takaya, J. Am. Chem. Soc. 1986, 108, 7117Ϫ7119.
[16c] R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, N. Sayo,
H. Kumobayashi, S. Akutagawa, J. Am. Chem. Soc. 1987, 109,
[16d]
5856Ϫ5858.
M. Kitamura, T. Ohkuma, S. Inoue, N. Sayo,
Weighting scheme of the form
w ϭ wЈ{1 Ϫ [(||Fo| Ϫ |Fc||)/
H. Kumobayashi, S. Akutagawa, T. Ohta, H. Takaya, R.
6σ(Fo)]2]}2 with wЈ
ϭ
1/
ΣrArTr(X) with coefficients
3.19, 1.59 and 2.51 for
Chebychev series for which
X ϭ Fc/Fc,max
Noyori, J. Am. Chem. Soc. 1988, 110, 629Ϫ631.
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T. Ikariya, Y. Ishii, H. Kawano, T. Arai, M. Saburi, S.
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a
.
1940
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1931Ϫ1941

Synthesis of SYNPHOS
FULL PAPER
C. J. A. Daley, S. H. Bergens, J. Am. Chem. Soc. 2002, 124,
3680Ϫ3691.
P. Dierkes, P. W. N. M. van Leeuwen, J. Chem. Soc., Dalton.
Trans. 1999, 1519Ϫ1529.
Energy differences were quite low (2 kcal/mol), but these values
are representative for two diastereoisomeric model transition
states.
[18] [18a]
[23]
[24]
[25]
ˆ
V. Ratovelomanana-Vidal, J.-P. Genet, J. Organomet.
[18b]
Chem. 1998, 567, 163Ϫ171.
V. Ratovelomanana-Vidal, J.-
P. Genet, Can. J. Chem. 2000, 78, 846Ϫ851. [18c] V. Ratovelom-
ˆ
anana-Vidal, C. Girard, R. Touati, J.-P. Tranchier, B. Ben Has-
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sine, J.-P. Genet, Adv. Synth. Catal. 2003, 345, 261Ϫ274.
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ˆ
J.-P. Genet, C. Pinel, V. Ratovelomanana-Vidal, S. Mallart,
X. Pfister, M. C. Cano de Andrade, J.-A. Laffitte, Tetrahedron:
Asymmetry 1994, 5, 665Ϫ674. [19b] J.-P. Genet, C. Pinel, V. Ra-
B. Heiser, E. A. Broger, Y. Crameri, Tetrahedron: Asymmetry
1991, 2, 51Ϫ62.
[26]
ˆ
tovelomanana-Vidal, S. Mallart, X. Pfister, L. Bischoff, M. C.
Cano de Andrade, S. Darses, C. Galopin, J.-A. Laffitte, Tetra-
hedron: Asymmetry 1994, 5, 675Ϫ690.
[27] [27a]
For thioketones, see: J.-P. Tranchier, V. Ratovelomanana-
[19c]
ˆ
ˆ
J.-P. Genet, Re-
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1996, p. 31Ϫ51.
38, 2951Ϫ2954. [27b] For β-keto sulfones, see: P. Bertus, P. Phan-
ˆ
savath, V. Ratovelomanana-Vidal, J.-P. Genet, A. R. Touati,
[20]
[21]
ˆ
D. Blanc, V. Ratovelomanana-Vidal, J.-P. Gillet, J.-P. Genet, J.
T. Homri, B. Ben Hassine, Tetrahedron: Asymmetry 1999, 10,
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See Exp. Sect. for a typical procedure.
1369Ϫ1380. [27c] For phosphonic acids, see: J. C. Henry, D. Lav-
ˆ
ergne, V. Ratovelomanana-Vidal, J.-P. Genet, I. P. Beletskaya,
[22] [22a] For [(BINAP)PdCl2], see: F. Ozawa, A. Kubo, Y. Matsum-
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ganometallics 1993, 12, 4188Ϫ4196. [22b] T. Hayashi, Y. Kobori,
M. Kumada, T. Higuchi, K. Hirotsu, J. Am. Chem. Soc. 1984,
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T. M. Dolgina, Tetrahedron Lett. 1998, 39, 3473Ϫ3476.
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ˆ
823Ϫ826.
Received November 14, 2002
Eur. J. Org. Chem. 2003, 1931Ϫ1941
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1941