SYNPHOS, a new chiral diphosphine ligand: Synthesis, molecular modeling and application in asymmetric hydrogenation

Article abstract of DOI:10.1016/S0040-4039(02)02637-0

A new optically active diphosphine ligand, [(5,6),(5′,6′)-bis(ethylenedioxy)biphenyl-2,2′-diyl]bis (diphenylphosphine) (SYNPHOS) has been synthesized and used in ruthenium-catalyzed asymmetric hydrogenation. This new ligand has been compared to other diphosphines (BINAP and MeO-BIPHEP), regarding their dihedral angles and the enantioselectivity in the ruthenium mediated hydrogenation reaction.

Full text of DOI:10.1016/S0040-4039(02)02637-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 823–826
SYNPHOS®, a new chiral diphosphine ligand: synthesis,
molecular modeling and application in asymmetric hydrogenation
Se´bastien Duprat de Paule,a Se´verine Jeulin,a Virginie Ratovelomanana-Vidal,a Jean-Pierre Geneˆt,a,*
Nicolas Championb and Philippe Dellisb
aLaboratoire de Synthe`se Se´lective Organique et Produits Naturels, UMR 7573, Paris, France
bSYNKEM S.A.S., Chenoˆve, France
Received 18 November 2002; accepted 20 November 2002
Abstract—A new optically active diphosphine ligand, [(5,6),(5%,6%)-bis(ethylenedioxy)biphenyl-2,2%-diyl]bis(diphenylphosphine)
(SYNPHOS®) has been synthesized and used in ruthenium-catalyzed asymmetric hydrogenation. This new ligand has been
compared to other diphosphines (BINAP and MeO-BIPHEP), regarding their dihedral angles and the enantioselectivity in the
ruthenium mediated hydrogenation reaction. © 2003 Elsevier Science Ltd. All rights reserved.
The search for new chiral ligands capable of high
enantioselectivity in homogeneous catalysis is a current
challenge in applied chemical research.1 Development
of optically active phosphine ligands, especially C2-
chiral atropoisomeric diphosphines, like BINAP2 or
MeO-BIPHEP3 (Fig. 1) were used in late transition-
metal complexes as (pre)catalysts and provided a great
advancement in asymmetric hydrogenation.4 However,
no universal system, i.e. a chiral ligand chelated to a
metal, has yet been found, since asymmetric transfor-
mations are often substrate-dependent. In our continu-
ous interest for the transition-metal-catalyzed
enantioselective hydrogenation reactions,4c–e,5 we have
designed new chiral diphosphine ligands in the last few
years.6
Since
atropoisomeric
ligands
bearing
heteroatoms like MeO-BIPHEP, CnTunaPhos7 or
SEGPHOS8 have shown to provide excellent enantio-
selectivity in the ruthenium-catalyzed hydrogenations,
we have turned our attention to oxygen-based diphos-
phines. We report here the synthesis of a new atropo-
isomeric ligand bearing a benzodioxane core, hereafter
named SYNPHOS®,9 the study of its structural proper-
ties via molecular modeling and its use in ruthenium-
mediated hydrogenation. During the preparation of this
manuscript, this ligand was independently synthesized
by Chan et al.10
As illustrated in Scheme 1, 1,2-ethylenedioxybenzene 1
was selectively brominated with N-bromosuccinimide in
DMF to afford 4-bromo-1,2-ethylenedioxybenzene 2 in
quantitative yield. Phosphorylation of compound 2 was
achieved by a sequence of lithiation, addition of
chlorodiphenylphosphine and oxidation with hydrogen
peroxide to provide (3,4-ethylenedioxyphenyl)diphenyl-
phosphine oxide 3 in 90% yield. Ortholithiation of
compound 3 and further oxidative coupling with anhy-
drous ferric chloride furnished [(5,6),(5%,6%)-bis(ethylene-
dioxy)biphenyl-2,2%-diyl]bis(diphenylphosphine oxide) 4
in 50% yield. The optical resolution of rac-4 afforded,
Figure 1.
Keywords: diphosphine ligand; molecular modeling; asymmetric
hydrogenation; ruthenium.
* Corresponding author. Fax: +33-1-44-071062; e-mail: genet@
ext.jussieu.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02637-0

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S. Duprat de Paule et al. / Tetrahedron Letters 44 (2003) 823–826
Scheme 1. (a) NBS, DMF, rt, 100%; (b) (1) n-BuLi, THF, −70°C (2) ClPPh2, −70°C to rt (3) H2O2, MeOH, 0°C, 90%; (c) (1)
t-BuLi, THF, −100 to −70°C (2) FeCl3, −70°C to rt, 50%; (d) (1) (−)-DBTA, CHCl3:AcOEt=1:3, fractionnal crystallization; then
(+)-DBTA, CHCl3:AcOEt=1:3, fractionnal crystallization (2) KOH, 70%; (e) HSiCl3, Bu3N, xylene, 140°C, 91%.
either (−)-4 with (2R,3R)-(−)-O,O%-dibenzoyltartaric
acid [(−)-DBTA], or (+)-4 with (2S,3S)-(+)-O,O%-di-
benzoyltartaric acid [(+)-DBTA] in 70% yield based on
rac-4. The absolute configuration of (−)-4 was deter-
mined by X-ray analysis of the complex of (−)-4 with
(−)-DBTA. From the internal comparison with (−)-
DBTA, the absolute configuration of (−)-SYNPHOS®
oxide ((−)-SYNPHOSO2) is defined to be S (Fig. 2).
Like in the MeO-BIPHEP series,3a a ‘through process’
3“(RS)-4“(R)-4 and (S)-4 was also developed,
enabling us to recover the unreacted starting material 3
by simple concentration of the filtrate at the end of step
(d). Reduction of the resolved 4 was performed by
heating with an excess of HSiCl3 in xylene in the
presence of Bu3N in yields of 91–98% for (S)-(−)-5 and
(R)-(+)-5.
(S)-(−)-4 and (R)-(+)-4 were enantiomerically pure
(>99% e.e.) according to HPLC (Chiralcel OD column).
Furthermore, subsequent oxidation of diphosphines
(S)-(−)-5 and (R)-(+)-5 with hydrogen peroxide showed
no racemization during the reduction process, accord-
ing to the enantiomeric purity determined by HPLC.
The enantiomeric purity of diphosphines (−)-5 and
1
(+)-5 was also confirmed by the assignment of the H
NMR shifts of the in situ formed Pd complex with (+)-
di-m-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]-
dipalladium.11,12 It has to be noted that the absolute
configuration of (−)-4 obtained in the resolution step
with (−)-DBTA is also in agreement with the results of
Saito13 (SEGPHOS series) and Schmid3a (MeO-
BIPHEP series). When (−)-DBTA is used as the resolv-
ing agent, the absolute configuration of the diphosphine
oxide thus obtained is S, in the case of SEGPHOS and
diMeO-BIPHEP. In the case of MeO-BIPHEP and
triMeO-BIPHEP, the absolute configuration of the
diphosphine oxide thus obtained is opposite, i.e. R. The
absolute configuration of the diphosphine oxide derived
from bisbenzodioxanPhos obtained by Chan et al. with
(−)-DBTA was R.10
Like Heiser, Broger and Crameri,14 we had noticed
through several examples in the past few years that
MeO-BIPHEP ligand exhibited higher enantioselectivi-
ties, comparing to BINAP ligand, in the ruthenium-
Figure 2. X-Ray drawing of (−)-DBTA/(−)-(S)-4 (Chem3D
representation, H omitted for clarity). The crystal consists of
polymeric chains of alternating SYNPHOSO2 and DBTA
molecules connected by hydrogen bonds.
mediated hydrogenation reactions of
a series of
functionalized ketones, e.g. thioketones, b-ketosulfones,
fluorous b-ketoesters and phosphonic acid.15 It is now
well established that steric7,13 and electronic3b effects

S. Duprat de Paule et al. / Tetrahedron Letters 44 (2003) 823–826
825
Figure 4. Ketone substrates and correlation q/e.e.
SYNPHOS®), by a CAChe MM2 calculation method.
This method is only based on the steric effects but not
on the electronic properties of the model. The results
are shown in Table 1.
Figure 3. Ruthenium-mediated hydrogenation intermediate
model (CAChe MM2 representation, H omitted for clarity).
The calculated dihedral angles decrease in the following
order: BINAP, MeO-BIPHEP and SYNPHOS®.
Table 1. Dihedral angles of diphosphines in Ru-complexes
Diphosphine ligand
Dihedral angle, q (°)
We have then compared these ligands in the hydrogena-
tion of several substrates (Scheme 2), in order to deter-
mine the influence of the dihedral angle on the
enantioselectivities. All hydrogenation reactions were
conducted twice, and in the same conditions of pres-
sure, temperature and time (24 h) for each ligand, with
1 mol% of catalyst.17 The results are summarized in
Table 2.
BINAP
80
76
75
MeO-BIPHEP
SYNPHOS®
play a crucial role. Thus, we decided to look at the
dihedral angle of the binaphthyl or biphenyl systems of
the atropoisomeric ligands. The steric considerations
based on the effect of varying the dihedral angle (q) in
biaryl backbone are expected to explain the differences
in the enantioselectivities. We decided to minimize the
energy of a ruthenium-mediated hydrogenation inter-
mediate model,16 as shown in Figure 3. This model
represents an intermediate model-complex formed of
RuHCl[(S)-Binap] and methylacetoacetate. Dihedral
angles have been measured in the models, bearing three
diphosphine ligands (BINAP, MeO-BIPHEP and
As shown in Figure 4, the enantioselectivities in the
hydrogenation of the selected substrates are remarkably
influenced by the dihedral angle of the ligand. The
narrower dihedral angle, the higher the enantioselectivi-
ties. When the catalysts bears a ligand with a narrow
dihedral angle, the interactions between the steric bulk
of the diphenylphosphino group and the substrate are
enhanced, and thereby, the enantioselectivities are
much higher.
Scheme 2. Asymmetric hydrogenation of functionalized ketones.
Table 2. Asymmetric hydrogenation results
Substratea
Ligand
Solvent
H2 (bar)
T (°C)
e.e. (BINAP)b (%)
e.e. (MeO-BIPHEP)b (%)
e.e. (SYNPHOS®)b (%)
a
b
c
d
e
(S)
(S)
(R)
(R)
(S)
EtOH
EtOH
MeOH
EtOH
MeOH
20
20
20
10
30
99
99
50
80
65
23
44
72
87
89
40
57
90
93
96
49
63
92
97
97
a Conversion rates were determined by 1H NMR (100%).
b The enantiomeric excess was determined by GC analysis (Lipodex A for substrates a–d and Hydrodex-b-G-TBDM for substrate e).

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S. Duprat de Paule et al. / Tetrahedron Letters 44 (2003) 823–826
In summary, we have described the synthesis, character-
ization and use of a new and very efficient atropo-
isomeric diphosphine ligand, SYNPHOS®. We also
confirmed that the dihedral angles, in diphosphine lig-
ands from the same family, influence clearly the enan-
tioselectivities in the ruthenium-mediated hydrogena-
tion reactions.
7. Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org.
Chem. 2000, 65, 6223.
8. Saito, T.; Sayo, N.; Xiaoyaong, Z.; Yokozawa, T.
(Takasago International Corporation), EP 0,850,945,
1998.
9. Duprat de Paule, S.; Champion, N.; Vidal, V.; Genet, J.
P.; Dellis, P. French Patent 0,112,499; PCT FR02/03146.
10. Pai, C. C.; Li, Y. M.; Zhou, Z. Y.; Chan, A. S. C.
Tetrahedron Lett. 2002, 43, 2789.
11. (a) Otsuka, S.; Nakamura, T.; Kano, T.; Tani, K. J. Am.
Chem. Soc. 1971, 93, 4301; (b) Tani, K.; Brown, L. D.;
Ahmed, J.; Ibers, J. A.; Yokota, M.; Nakamura, T.;
Otsuka, S. J. Am. Chem. Soc. 1977, 99, 7876.
12. (a) Roberts, N. K.; Wild, S. B. J. Am. Chem. Soc. 1979,
101, 6254; (b) Roberts, N. K.; Wild, S. B. J. Chem. Soc.,
Dalton Trans. 1979, 2015.
13. Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo,
N.; Miura, T.; Kumobayashi, H. Adv. Synth. Catal. 2001,
343, 264.
14. Heiser, B.; Broger, E. A.; Crameri, Y. Tetrahedron:
Asymmetry 1991, 2, 51.
Acknowledgements
CNRS and Synkem S.A.S. are gratefully thanked for a
doctoral fellowship. We deeply thank Dr. A. Solladie´-
Cavallo, from the Department of Fine Organic Chem-
istry (ECPM, Strasbourg, France) for her kind
permission to use molecular modeling facilities. We also
thank Dr. R. Schmid (Hoffmann-La Roche) for a
generous gift of (S)- and (R)-MeO-BIPHEP.
15. (a) For thioketones, see: Tranchier, J.-P.; Ratovelo-
manana-Vidal, V.; Genet, J.-P.; Tong, S.; Cohen, T.
Tetrahedron Lett. 1997, 38, 2951; (b) For b-ketosulfones,
see: Bertus, P.; Phansavath, P.; Ratovelomanana-Vidal,
V.; Genet, J.-P.; Touati, A. R.; Homri, T.; Ben Hassine,
B. Tetrahedron: Asymmetry 1999, 1369; (c) For fluorous
b-ketoesters, see: Blanc, D.; Ratovelomanana-Vidal, V.;
Gillet, J.-P.; Genet, J.-P. J. Organomet. Chem. 2000, 603,
128; (d) For phosphonic acids, see: Henry, J. C.;
Lavergne, D.; Ratovelomanana-Vidal, V.; Genet, J.-P.
Tetrahedron Lett. 1998, 39, 3473.
References
1. Kagan, H. B. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. I, Chapter 2, p. 9.
2. For a review, see: Noyori, R.; Takaya, H. Acc. Chem.
Res. 1990, 23, 345 and references cited therein.
3. (a) Schmid, R.; Foricher, J.; Cereghetti, M.; Scho¨nholzer,
P. Helv. Chim. Acta 1991, 74, 370; (b) Schmid, R.;
Broger, E. A.; Cereghetti, M.; Crameri, Y; Foricher, J.;
Lalonde, M.; Mu¨ller, R. K.; Scalone, M.; Schoettel, G.;
Zutter, U. Pure Appl. Chem. 1996, 68, 131.
4. (a) Noyori, R. Asymmetric Catalysis in Organic Synthe-
sis; Wiley & Sons: New York, 1994; pp. 1–93; (b)
Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; Wiley & Sons: New
York, 2000; pp. 1–110; (c) Genet, J.-P. Reductions in
Organic Synthesis; ACS Symposium Series 641, 1996; pp.
31–51; (d) Ratovelomanana-Vidal, V.; Genet, J.-P. J.
Organomet. Chem. 1998, 567, 163; (e) Ratovelomanana-
Vidal, V.; Genet, J.-P. Can. J. Chem. 2000, 78, 846.
5. (a) Genet, J.-P.; Pinel, C.; Ratovelomanana-Vidal, V.;
Mallart, S.; Pfister, X.; Cano de Andrade, M. C.; Laffitte,
J. A. Tetrahedron: Asymmetry 1994, 5, 665; (b) Rauten-
strauch, V.; Grazi, P.; Vanhessche, K. P. M.; Lenoir, J.
Y.; Genet, J. P.; Woles, J. A.; Bergens, S. H. Angew.
Chem., Int. Ed. 2000, 39, 1992.
16. Recently, ruthenium (alkoxide) hydride intermediates
have been identified. See: Daley, C. J. A.; Bergens, S. H.
J. Am. Chem. Soc. 2002, 124, 3680.
17. General procedure for asymmetric hydrogenation: (S)-
SYNPHOS® (7.1 mg, 0.011 mmol) and (COD)Ru(h3-
(CH2)2CCH3)2 (3.2 mg, 0.01 mmol) were placed in a 10
mL flask, and 1 mL of degassed anhydrous acetone was
added dropwise. A methanolic solution of HBr (122 mL,
0.18 M) was added dropwise to the suspension. The
reaction mixture was stirred at room temperature for
about 30 min and a resulting orange suspension was
observed. The solvent was removed under vacuum. The
brown solid residue was used without further purification
as a catalyst for the hydrogenation reaction of the desired
substrate (1 mmol) in 2 mL of MeOH or EtOH. The
reaction vessels were placed in a 500 mL stainless steel
autoclave, which was adjusted to the desired pressure and
temperature for 24 h. The methanol was concentrated
and the crude product was filtrated on a short pad of
silica gel (cyclohexane/AcOEt, 1:1). Conversion and e.e.
6. (a) For Digm-BINAP, see: Guerreiro, P.; Ratovelo-
manana-Vidal, V.; Genet, J. P.; Dellis, P. Tetrahedron
Lett. 2001, 42, 3423; (b) For MeO-NaPhePHOS, see:
Michaud, G.; Bulliard, M.; Ricard, L.; Genet, J. P.;
Marinetti, A. Chem. Eur. J. 2002, 8, 3327.
1
were determined by H NMR and chiral GC.