SYNPHOS: A new atropisomeric diphosphine ligand. From laboratory-scale synthesis to scale-up development

Article abstract of DOI:10.1021/op034016w

A new optically active diphosphine ligand, [(5,6),(5′,6′)-bis(ethylenedioxy)biphenyl.2,2′-diyl]bis (diphenylphosphine) (SYNPHOS) has been synthesized. Laboratory-scale synthesis and scale-up development of this ligand are described herein. This new atropisomeric diphosphine was also used in ruthenium-catalyzed asymmetric hydrogenation.

Full text of DOI:10.1021/op034016w

Organic Process Research & Development 2003, 7, 399−406
SYNPHOS: a New Atropisomeric Diphosphine Ligand. From Laboratory-scale
Synthesis to Scale-up Development
Se´bastien Duprat de Paule,† Se´verine Jeulin,† Virginie Ratovelomanana-Vidal,† Jean-Pierre Geneˆt,*,† Nicolas Champion,*,‡
Gilles Deschaux,‡ and Philippe Dellis‡
Laboratoire de Synthe`se Se´lectiVe Organique et Produits Naturels, ENSCP, 11 rue Pierre et Marie Curie,
75231 Paris Cedex 05, France, and SYNKEM S.A.S., 47 rue de LongVic, 21301 ChenoˆVe Cedex, France
Abstract:
starting from commercial benzo-1,4-dioxane (Scheme 1).7
In the first step, benzo-1,4-dioxane 1 was readily brominated
with N-bromosuccinimide in DMF in quantitative yield.
Bromobenzo-1,4-dioxane 2 was then lithiated by lithium-
halogen exchange with 1.1 equiv of n-butyllithium at -70
°C in THF, further reacted with 1.1 equiv of ClPPh2 and
finally oxidized with hydrogen peroxide to afford phosphine
oxide 3 as a pale yellow solid in high yields. Dimerization
of compound 3 was a key step for the synthesis of
SYNPHOS ligand. The first aim was to achieve ortholithia-
tion of compound 3. The lithiated intermediate was oxidized
by FeCl3 to provide bis(phosphine oxide) 4. Best results were
obtained with t-BuLi at low temperature (-100 °C then -70
°C), under thermodynamically controlled conditions,8 and
compound 4, hereafter named SYNPHOSO2 was obtained
in 50% yield. Racemic SYNPHOSO2 was resolved with O,O-
dibenzoyltartaric acid9 [(+)- or (-)-DBTA] by fractional
crystallization. A solution of racemic SYNPHOSO2 in
chloroform and a solution of (-)-DBTA in ethyl acetate were
mixed at room temperature (CHCl3/AcOEt, 1:3). After a few
minutes, precipitation of a 1:1 complex of (-)-DBTA and
(S)-SYNPHOSO2 was observed. Treatment of the tartrate
complex with aqueous base (1 N KOH) provided enantio-
merically enriched (S)-SYNPHOSO2 (ee ) 70%, according
to HPLC, Chiralcel OD column). Enantiomerically pure
(S)-SYNPHOSO2 was obtained by repeating this operation
four times, in 70% yield based on rac-4. Enantiomerically
enriched (R)-SYNPHOSO2 was recovered from the mother
liquor after treatment with aqueous base. Similary, enantio-
merically pure (R)-SYNPHOSO2 was then obtained from
enantiomerically enriched (R)-4 by using (+)-DBTA in 70%
yield based on rac-4. The final step in the synthetic route
was the reduction of bis(phosphine oxide) 4. This was
accomplished by treatment of SYNPHOSO2 with trichlo-
rosilane-tributylamine in refluxing xylene producing
(-)-(S) and (+)-(R)-SYNPHOS with a global yield of 28%
from 1.
A new optically active diphosphine ligand, [(5,6),(5′,6′)-bis-
(ethylenedioxy)biphenyl-2,2′-diyl]bis(diphenylphosphine) (SYN-
PHOS) has been synthesized. Laboratory-scale synthesis and
scale-up development of this ligand are described herein. This
new atropisomeric diphosphine was also used in ruthenium-
catalyzed asymmetric hydrogenation.
Introduction
In the last two decades, considerable efforts have been
undertaken for the design of new ligands to develop highly
efficient metal-catalyzed asymmetric transformations, and
this topic remains a current challenge in applied chemical
research.1 Development of optically active phosphine ligands,
especially C2-chiral atropisomeric diphosphines, such as
BINAP2 or MeO-BIPHEP,3 provided a great advancement
in asymmetric hydrogenation. Since atropisomeric ligands
bearing heteroatoms such as MeO-BIPHEP or SEGPHOS4
have demonstrated excellent enantioselectivity in the ruthe-
nium-catalyzed hydrogenations, we have turned our attention
to oxygen-based diphosphines. We report here the laboratory-
scale synthesis of a new atropisomeric ligand bearing a
benzodioxane core, hereafter named SYNPHOS,5 its scale-
up development, and its use in ruthenium-mediated hydro-
genation. In the meantime, Chan and co-workers6 have
synthesized this ligand as well.
Laboratory-Scale Synthesis. The synthesis of SYN-
PHOS ligand was accomplished in a five-step procedure
* Authors for correspondence. E-mail: (J.-P.G) genet@ext.jussieu.fr; (N.C)
n.champion@fournier.fr.
† Laboratoire de Synthe`se Organique Se´lective et Produits Naturels.
‡ SYNKEM S.A.S.
(1) (a) Kagan, H. B. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; Vol. I,
Chapter 2, p 9. (b) Ojima, I. Catalytic Asymmetric Synthesis; John Wiley
and Sons: New York, 2000.
(2) (a) Miyashita, A.; Yasuda A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.;
Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932. (b) Noyori, R.; Takaya, H.
Acc. Chem. Res. 1990, 23, 345.
(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) Saito, Sayo, T. N.; Xiaoyaong, Z.; Yokozawa, T. (Takasago International
Corporation). EP 0850945, 1998. (b) Saito, T.; Yokozawa, T.; Ishizaki, T.;
Moroi, T.; Sayo, N.; T. Miura, T.; Kumobayashi, H. AdV. Synth. Catal.
2001, 343, 264.
Scale-Up Synthesis. The laboratory synthesis was suitable
for producing several grams of ligand but would be
problematic for producing kilograms for several reasons. The
main drawback was the low yielding t-BuLi/FeCl3 coupling
step. At best, only 50% of compound 4 was obtained along
(7) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-Vidal, V.; Geneˆt, J.-P.;
Champion, N.; Dellis, P. Tetrahedron Lett. 2003, 44, 823.
(8) Brown, J. M.; Woodward, S. C. J. Org. Chem. 1991, 56, 6803.
(9) Brunner, H.; Pieronczyk, W.; Scho¨nhammer, B.; Streng, K.; Bernal, I.; Korp
J. Chem. Ber. 1981, 114, 1137.
(5) Duprat de Paule, S.; Champion, N.; Vidal, V.; Geneˆt, J.-P.; Dellis, P. French
Patent 0112499; PCT FR02/03146.
(6) Pai, C. C.; Li, Y. M.; Zhou, Z. Y.; Chan, A. S. C. Tetrahedron Lett. 2002,
43, 2789.
10.1021/op034016w CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/16/2003
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Scheme 1. SYNPHOS laboratory synthesis
Scheme 2
Scheme 3
with starting material. Though the uncoupled compound 3
could be recovered from the mother liquors during the
resolution step and recycled, a higher conversion would have
been required. We were also interested in performing the
reaction at a higher temperature, -100 °C being not
compatible with our facilities. Replacement of the very
flammable t-BuLi by a cheaper and safer reagent was also a
requirement. Furthermore substantial degradation of the
dioxane moiety was observed with t-BuLi in THF above -70
°C.10
n-BuLi metalation step and to use magnesium as cheaper
reagent.
LDA at low temperature in THF gave the best results for
the ortholithiation/iodination sequence. The ortholithia-
tion temperature and the sense of addition, i.e., normal or
inverted addition of the iodine solution, were two critical
parameters to obtain the expected compound 6 with good
conversion. For instance, ortholithiation of compound 3
for 3 h at -70 °C and quenching this solution at -70 °C
with iodine solution in THF (direct addition) gave the
expected compound 6 with only 35-40% conversion along
with starting material and a complexe mixture of benzo-
dioxane-ring-opening byproducts. Increasing the ortholithia-
tion temperature to -40 °C lowered the formation of
compound 6 and favored the formation of degradation
byproducts. On the other hand, ortholithiation of compound
3 for 3 h at -70 °C, followed by the addition of the resulting
At this point, we decided to investigate another approach
using a two-step sequence of ortholithiation-iodination3a,6 of
compound 3 and then Ullmann reaction of the corresponding
iodide 6 to get racemic compound 4 (Schemes 2 and 3).
Starting from compound 2, we alternatively obtained phos-
phine oxide 3 with 78% yield via the Grignard reagent which
was reacted with chlorodiphenylphosphine (technical grade)
and subsequently oxidized by aqueous hydrogen peroxide.
This sequence, which had previously been described,11
advantageously allowed us to suppress the low temperature
(10) (a) Ranade, A. C. Jayalakshmi S. Chem. Ind. 1978, 234. (b) Mattson, R. J.;
Sloan, C. P.; Lockart, C. C.; Catt, J. D.; Gao, Q.; Huang, S. J. Org. Chem.
1999, 64, 8004.
(11) (a) Laue, C.; Schro¨der, G.; Arlt, D. U.S. Patent 5,710,339, 1998. (b) Foricher,
J.; Schmid, R. EP 0926152 A1, 1998.
400
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Scheme 4. Asymmetric hydrogenation of functionalized
ketones
solution to a iodine solution (inverted addition) at -60 °C
gave satisfactory conversion (typically 80-85% by HPLC).
The reaction was successfully achieved even when the
lithiated derivative of compound 3 was added to the iodine
solution up to a temperature of -10 °C. The crude reaction
mixture was directly used in the Ullmann coupling step using
copper powder in DMF (Scheme 3). After 2.5 h at 110 °C
no more starting material was detected and racemic com-
pound 4 was obtained along with compound 3 in a 80/20
ratio (4/3), according to the HPLC. Reduction of compound
6, which is a common side reaction in Ullmann conditions,
did not exceed 5 to 10%, depending on the experiment and
taking into account that compound 3 was already present in
crude compound 6 (typically 10 to 15% by HPLC).
The resolution step was optimized to shorten and improve
the initial enrichment process (five successive resolutions,
70% yield based on rac-4). The conditions described earlier
(formation of the (-)-DBTA/(S)-SYNPHOSO2 complex in
AcOEt/CHCl3 mixture) were indeed difficult to control on
a larger scale and if the reaction mixture was not filtered
within a few minutes of the precipitate forming, the enrich-
ment was not efficient. Alternatively, if the reaction mixture
was maintained for a longer period (at least 1 h at 20 °C),
the 50/50 mixture of both (-)-(S)-4/(-)-DBTA and (+)-
(R)-4/(-)-DBTA complexes was obtained with a 95% yield
as a white solid after filtration. This procedure was actually
advantageous both to purify the crude reaction mixture from
the Ullmann coupling step and to recover unreacted com-
pound 3 from the mother liquor. Optically pure (+)-(R)-4/
(-)-DBTA complex was finally obtained after two slurries
of the 50/50 complexes mixture in CH2Cl2. Destruction of
the complex with potassium hydroxide afforded enantiopure
(+)-(R)-4 in 79% yield based on rac-4. The combined
filtrates containing the soluble (-)-(S)-4/(-)-DBTA was
treated with 1 N KOH. After usual workup (see Experimental
Section), the resulting white solid was then similarly treated
with (D)-(+)-dibenzoyltartaric acid, providing enantiopure
(-)-(S)-5 in 78% yield based on rac-4.
Using SYNPHOS, we investigated the hydrogenation
reactions of various carbonyl substrates: â-keto esters, R-keto
esters, and functionalized ketones. Hydrogenations were
carried out on a 1-mmol scale using 1 mol % catalyst, in a
stainless steel autoclave. The conversions were determined
by 1H NMR spectroscopy, and enantiomeric excesses of the
products were determined by chiral GC or HPLC. The results
are given in Table 1.
In all cases, complete conversion was obtained. The
catalytic system based on SYNPHOS ligand gave high
enantiomeric excesses with â-keto esters under 4 bar of
hydrogen and at 50 °C, providing the corresponding substi-
tuted â-hydroxy esters with enantiomeric excesses ranging
from 97 to >99% for the aromatic compound (entry 5) and
the aliphatic compounds (entries 1-4), respectively. Ruthe-
nium-mediated hydrogenations of fluorinated substrates are
known to give poor ee even at high temperature (99 °C),14
but SYNPHOS ligand displayed a higher enantioselectivity
of 49% (entry 6, 23% with BINAP ligand).14 Enantioselec-
tivities, regarding other ketone substrates, turned out to be
very high, too. R-Hydroxy esters, resulting from the asym-
metric hydrogenation of the corresponding carbonyl com-
pounds, were obtained with enantiomeric purities of 92-
94% under 20 bar of hydrogen and at 50 °C (entries 7-8).
Various functionalized ketones, such as hydroxyacetone
(entry 9), a â-thioketone (entry 10), a â-keto phosphonate
(entry 11), and a 1,3-diketone (entry 12), were also hydro-
genated with ee above 97%.
Asymmetric Hydrogenation. Ruthenium-catalyzed asym-
metric hydrogenation is known to be a very convenient
method for producing optically active alcohols and chiral
building blocks, especially with atropoisomeric diphos-
phine ligands.12 Based on an in situ procedure,13 catalysts
were prepared from commercially available [Ru(COD)-
(2-methylallyl)2] and SYNPHOS ligand by addition of a
methanolic solution of HBr in acetone as detailed in Scheme
4. After removal of the solvent in vacuo, these complexes
were used without further purification.
These complexes were also efficient using a substrate:
catalyst ratio up to 10 000 under 20 bar of hydrogen at 50
°C, providing pure (3R)-methyl hydroxybutanoate as shown
in Scheme 5.
Furthermore, SYNPHOS compared favorably with two
well-known atropisomeric diphosphine ligands BINAP and
MeO-BIPHEP, in ruthenium-catalyzed asymmetric hydro-
genation of several model substrates (Table 2) and using the
same in situ method for each catalyst preparation.13 Com-
parative hydrogenation reactions with these three ligands
were conducted using 1 mol % catalyst in the same
conditions of temperature, pressure, time, and concentration
(0.5 mmol/mL) for each substrate, and we observed that
SYNPHOS gave the highest enantioselectivities.7
(12) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley and
Sons: New York, 1994. (b) Noyori, R. Tetrahedron 1994, 50, 4259. (c)
Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; 2000; pp 1-110. (d) Noyori, R.; Ohkuma, T. Angew. Chem.,
Int. Ed. 2001, 40, 40. (e) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008.
(f) Ratovelomanana-Vidal, V.; Geneˆt, J.-P. J. Organomet. Chem. 1998, 567,
163. (g) Geneˆt, J.-P. Pure Appl. Chem. 2002, 74, 77.
(13) (a) Geneˆt, 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) Geneˆt, J.-P.; Pinel, C.; Ratovelomanana-Vidal, V.; Mallart, S.;
Pfister, X.; Bischoff, L.; Cano de Andrade, M. C.; Darses, S.; Galopin, C.;
Laffitte J.-A. Tetrahedron: Asymmetry 1994, 5, 675. (c) Geneˆt, J.-P.
Reductions in Organic Synthesis; ACS Symposium Series 641; American
Chemical Society: Washington, DC, 1996; pp 31-51.
(14) Blanc, D.; Ratovelomanana-Vidal, V.; Gillet, J.-P.; Geneˆt J.-P. J. Organomet.
Chem 2000, 603, 128.
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Table 1. Hydrogenation results
a All conversions were 100%, according to 1H NMR. b Enantiomeric excess measured by chiral GC.
Scheme 5. Multigram-scale asymmetric hydrogenation of
methyl acetoacetate
Experimental Section
General Remarks. 1H NMR spectra were recorded on a
Bruker AC 200 at 200 MHz or on a Avance 400 at 400 MHz,
13C NMR spectra were recorded on a Bruker AC 200 at 50
MHz and 31P NMR spectra were recorded on a 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 electronic impact (EI), chemical ionization with ammonia
(DCI/NH3), or electrospray (ESI) for compounds (-)-(S)-5
and (+)-(R)-5. Optical rotations were measured on a Perkin-
Elmer 241 polarimeter at 589 nm (sodium lamp). Melting
points (mp) were determined on a Kofler melting point
apparatus. GC analyses were performed on a Hewlett-
Packard 5890 series II instrument connected to a Merck
D-2500 or D-2000 integrator, using flame ionization detector;
enantiomeric excesses were determined on chiral capillary
columns: Lipodex A, Hydrodex-â-6-TBDM, Chirasil-Val,
Megadex 5, or Chirasil-DEX CB. HPLC analyses of
Conclusions
In summary, we have reported here the synthesis of a
new atropisomeric chiral diphosphine ligand SYNPHOS that
proved to be very efficient when used in ruthenium-catalyzed
asymmetric hydrogenation with numerous substrates. A
scale-up route has been studied that relies on an ortholithia-
tion/iodination sequence and a subsequent Ullmann reaction
as the key steps. Following this sequence a “through process”
3 f 6 f rac-4 f (+)-4 or (-)-4 has been performed without
any purification by chromatography, providing an access to
enantiopure diphosphine 5 with a global yield of 34-40%
from 2.
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Table 2. Comparative study between SYNPHOS, MeO-BIPHEP and BINAP
1
compound 4 were conducted with Waters 600 system, using
Daicel chiral stationary phase column: Chiralcel OD, hexane/
2-propanol, 90:10.
oil (236.9 g, quantitative). H NMR (CDCl3): δ ) 4.25 (s,
4H), 6.74 (d, J ) 8.5 Hz, 1H), 6.93 (dd, J ) 8.5, 2.3 Hz,-
1H), 7.02 (d, J ) 2.3 Hz, 1H). 13C NMR (CDCl3): δ )
64.1, 112.7, 118.5, 120.1, 124.1, 142.8, 144.2. EI-MS m/z
81Br 216 (M)+.
4-Bromo-1,2-ethylenedioxybenzene 2. 1,2-Ethylene-
dioxybenzene (150 g, 1.10 mol) and anhydrous DMF (800
mL) were mixed at 0 °C in a 2-L double-jacket reactor
provided with a thermometer and a mechanical stirrer.
N-Bromosuccinimide (235.3 g, 1.32 mol) was added by
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 200 mL of CH2-
Cl2. The resulting filtrate was treated with 200 mL of a 30%
aqueous solution of Na2S2O3 and washed with brine. After
evaporation and distillation under reduced pressure (bp )
116 °C, 2 mbar), compound 2 was obtained as a colourless
(3,4-Ethylenedioxyphenyl)diphenylphosphine Oxide 3.
Magnesium turnings (14.9 g, 0.614 mol) were suspended in
45 mL of THF under nitrogen in a 1-L double-jacket reactor
provided with a condenser, thermometer, mechanical stirrer,
and dropping funnel with pressure compensation. The
reaction mixture was heated to 55 °C, and a few drops of
1,2-dibromoethane were added. A solution of 4-bromo-1,2-
ethylenedioxy-benzene 2 (120 g, 0.558 mol) in THF (240
mL) was then added to the suspension within 30 min while
stirring vigorously with the temperature being held at 60-
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65 °C. After completion of the dropwise addition, the
resulting gray solution was stirred at reflux for 2 h. The
reaction mixture was cooled to -8 °C and treated dropwise
within 2 h with a solution of 135.4 g (0.614 mol) of
chlorodiphenylphosphine in 270 mL of THF. After comple-
tion of the dropwise addition, the reaction mixture was heated
to 25 °C and held at this temperature for 2.5 h. Subsequently,
100 mL of methanol were added thereto from a dropping
funnel while stirring with the temperature rising to a
maximum of 37 °C. The reaction mixture was then cooled
to 0 °C, and 100 g of 35% hydrogen peroxide solution was
added dropwise at such a rate that the reaction temperature
did not exceed 30 °C. Shortly after completion of the
dropwise addition, the reaction was completed according to
TLC (AcOEt, UV detection). The reaction mixture was
treated with 100 mL of a saturated Na2S2O5 aqueous solution
following which, peroxide could no longer be detected. THF
was then distilled off under reduced pressure, and 500 mL
of dichloromethane was added. After stirring for 15 min,
the aqueous phase was separated, and the organic phase
extracted with 150 mL of 1 N hydrochloric acid. The aqueous
phase was separated and back-extracted with 250 mL of
dichloromethane. The combined organic phases were par-
tially concentrated by distillation under vacuum, and 800 mL
of dioxane was added. The concentration of the reaction
mixture was continued until 600 mL of dioxane remained.
The suspension was subsequently heated to 90 °C for
solubilisation, cooled within 45 min to 45 °C, maintained at
45 °C for 30 min, cooled to 20 °C within 1 h, and maintained
at 20 °C for 1 h. The white crystals were filtered off under
suction, washed with 100 mL of dioxane, and dried at 45
°C in vacuo overnight to provide 105.7 g (56.3%) of
compound 3 as a white solid. From the mother liquor,
dioxane was distilled off under reduced pressure until 200
mL remained. The suspension was subsequently heated to
60 °C for solubilisation and slowly cooled to 20 °C in 1 h
and maintained at 20 °C for 1 h. The white crystals were
filtered off under suction, washed with 20 mL of dioxane,
and dried at 45 °C in vacuo overnight to provide 40.9 g
(21.8%, combined yield 78.1%) of compound 3 as a white
solid. Mp ) 150-155 °C. 1H NMR (CDCl3): δ ) 4.26 (m,
4H), 6.95 (dd, J ) 11.8, 3.1 Hz,1H), 7.09-7.18 (m, 2H),
7.42-7.54 (m, 6H), 7.61-7.72 (m, 4H). 13C NMR
(CDCl3): δ ) 64.1, 64.4, 117.6 (d, J ) 14.6 Hz), 121.2 (d,
J ) 12.1 Hz), 125.5 (d, J ) 10.3 Hz), 128.2, 128.4, 131.7,
131.8, 132.0, 133.6, 143.3, 146.7. 31P NMR (CDCl3): δ )
30.10. CI-MS (pos) m/z 337 (M + H)+.
(0.297 mol) of iodine and 500 mL of dry THF. After stirring
for 1 h at -10 °C, the reaction mixture was heated to 20
°C, held for 1 h at 20 °C, and hydrolyzed with 400 mL of
20% aqueous solution of Na2S2O5. After stirring for 15 min
the aqueous phase was separated, and the organic phase was
distilled off under reduced pressure. The crude residue was
dissolved in 500 mL of dichloromethane, and 300 mL of 1
N sodium hydroxide was added. After stirring for 15 min
the aqueous phase was separated, and the organic phase
extracted with 150 mL of 1 N hydrochloric acid. After the
aqueous phase was separated, the organic phase was evapo-
rated under reduced pressure to give 70 g of a thick brown
1
oil. (1H NMR ratio 3/6 ) 16/84). H NMR (CDCl3): δ )
4.31 (m, 4H), 6.69 (dd, J ) 12.7, 8.7 Hz, 2H), 6.81(dd, J )
8.7, 2.8 Hz, 2H), 7.47-7.58 (m, 6H), 7.63-7.77 (m, 4H).
31P NMR (CDCl3): δ ) 34.42. CI-MS m/z 463 (M + H)+.
[(5,6),(5′,6′)-Bis(ethylenedioxy)biphenyl-2,2′-diyl]bis-
(diphenylphosphine oxide), SYNPHOSO2 4 from com-
pound 3. To a solution of 3 (30 g, 87 mmol) in dry THF
(600 mL) was added dropwise t-BuLi (65 mL, 1.5 M solution
in pentane, 90 mmol) at -100 °C. During 30 min, the
reaction temperature was raised to -70 °C, and the resulting
red solution was stirred for an additional 3 h at this
temperature. Anhydrous FeCl3 (19.8 g, 121.8 mmol) was then
added in one portion under a flow of argon at -70 °C. The
reaction temperature quickly rose 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 50 mL
of 1 N aqueous NaOH. After stirring for 30 min, the resulting
suspension was filtered on Celite, and the filter cake was
washed with CH2Cl2 (100 mL). The organic layer was
washed with water and brine, dried over MgSO4, filtered,
and concentrated. 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 AcOEt (180 mL) was added. In a few minutes, a
precipitate was formed. After filtration (the filtrate was
concentrated in vacuo to give starting material 3 (15 g, 50%)
as a pale yellow solid), the solids were suspended in CH2-
Cl2 (200 mL) and treated with 100 mL of 1 N aqueous KOH.
After stirring for 30 min, the clear organic layer was
separated, washed with water and brine, dried over MgSO4,
filtered, and evaporated to afford pure rac-4 (15 g, 50%) as
1
a white solid. Mp > 260 °C. H NMR (CDCl3): δ ) 3.42
(m, 2H), 3.70 (m, 2H), 3.92 (m, 2H), 4.06 (m, 2H), 6.64
(dd, J ) 13.3, 8.5 Hz, 2H), 6.77 (dd, J ) 8.5, 3.1 Hz, 2H),
7.26-7.31 (m, 4H), 7.35-7.55 (m, 12H), 7.65-7.70 (m,
4H). 13C NMR (CDCl3): δ ) 63.3, 63.9, 115.9 (d, J ) 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. 31P NMR (CDCl3): δ ) 30.97. CI-MS
m/z 671 (M + H)+. HRMS: calcd for C40H32O6P2 (M + H)
671.1752; found 671.1755.
[(5,6),(5′,6′)-Bis(ethylenedioxy)biphenyl-2,2′-diyl]bis-
(diphenylphosphine oxide), SYNPHOSO2 4 from Com-
pound 6. Sixty-eight grams of crude compound 6 (88%
purity, 0.129 mol) and 300 mL of DMF were placed under
nitrogen in a 0.5-L three-necked flask provided with a
(2-Iodo-3,4-ethylenedioxyphenyl)diphenylphosphine Ox-
ide 6. Compound 3 (50 g, 0.149 mol) and 500 mL of dry
THF were placed under nitrogen in a 1-L three-necked flask
provided with a thermometer, stirring bar, and dropping
funnel with pressure compensation. After cooling to -75
°C, 81.8 mL (0.164 mol) of lithium diisopropylamide (2 N
solution in heptane/THF/ethylbenzene) was added dropwise
with the temperature being held below -70 °C. After stirring
at -75 °C for 3.5 h, the reaction mixture was cannulated at
-10 °C over 30 min in a 2.5-L three-necked flask (provided
with a thermometer and a stirring bar) containing 75.5 g
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thermometer and a stirring bar. The reaction mixture was
heated to 110 °C, and 24.7 g (0.388 mol, 45 µm) of copper
powder were added. After stirring for 2.5 h at 110 °C the
reaction mixture was cooled to 20 °C and filtered, and the
solid residue was washed with 50 mL of DMF. The solvent
was distilled off from the filtrate under reduced pressure,
and the resulting oily residue was diluted in 300 mL of CH2-
Cl2, washed successively with 100 mL of saturated NH4Cl
solution and 100 mL of water. The solvent was distilled off
under reduced pressure to give 51.5 g of a thick brown oil
(HPLC ratio 3/4 ≈ 20/80).
[(5,6),(5′,6′)-Bis(ethylenedioxy)biphenyl-2,2′-diyl]bis-
(diphenylphosphine), SYNPHOS 5. To a 0.25-L three-
necked flask provided with a thermometer, a stirring bar,
and a dropping funnel with pressure compensation were
added under nitrogen 10 g of compound 4 (14.8 mmol), 100
mL of dry xylene, and 15.2 g of tributylamine (82.0 mmol).
To the resulting suspension were added dropwise at 20 °C
10.1 g of trichlorosilane (74.6 mmol). The resulting mixture
was then heated at 130 °C for 14 h. The reaction mixture
was cooled to 0 °C, and 100 mL of degassed 4 N aqueous
NaOH was added dropwise. After stirring for 30 min the
reaction mixture was heated to 20 °C, and 300 mL of
degassed CH2Cl2 was added. The reaction mixture was stirred
for 30 min. The organic layer was isolated, washed with 100
mL each of degassed distilled water and degassed brine, and
concentrated in vacuo. MeOH (100 mL) was then added,
and a white precipitate formed. The solid was filtered at 20
°C under nitogen and dried in vacuo for 3 h to afford 8.57
g (90.0%) of SYNPHOS 5 as a white solid.
Resolution of SYNPHOSO2 4. To a 1-L three-necked
flask provided with a thermometer, stirring bar, and dropping
funnel with pressure compensation were added 34 g (80%
purity, 40.6 mmol) of rac-SYNPHOSO2 4 and 340 mL of
CHCl3 under nitrogen. A solution of 16.8 g (46.9 mmol) of
(-)-O,O-dibenzoyltartaric acid in 800 mL of AcOEt was
added dropwise to the reaction mixture at 20 °C. After
stirring at 20 °C for 2 h, the white suspension was cooled to
0 °C, stirred a further 1 h at 0 °C, and filtered at 0 °C. The
resulting solid was washed with 100 mL of AcOEt and dried
under vacuum at 30 °C overnight to give a 50/50 mixture
(according to HPLC) of both (-)-(S)-4/(-)-DBTA and
(+)-(R)-4/(-)-DBTA complexes (39.6 g, 95%). The resulting
solid was then mixed with 490 mL of CH2Cl2 in a 1-L three-
necked-flask provided with a thermometer and a stirring bar.
After stirring for 2 h at 20 °C, the suspension was filtered,
and the filtrate was stored for the recovery of the other
enantiomer. The resulting solid was washed with 50 mL of
CH2Cl2 and dried at 30 °C under vacuum to give 17.8 g of
a white solid. An aliquot of the resulting white solid was
suspended in CH2Cl2 and treated with 1 N aqueous KOH.
After stirring for 15 min, the clear organic layer was
separated, washed with water, and evaporated to afford a
white solid (ee ) 94.4% according to HPLC). The solid was
once again mixed with 200 mL of CH2Cl2 in a 0.5-L three
necked flask provided with a thermometer and a stirring bar.
After stirring for 1.5 h at 20 °C, the suspension was filtered,
and the filtrate was stored for the recovery of the other
enantiomer. The resulting solid was washed with 40 mL of
CH2Cl2 and dried at 30 °C under vacuum to give 16.3 g of
a white solid. The resulting white solid was then suspended
in 200 mL of CH2Cl2 and treated with 150 mL of 1 N
aqueous KOH. After stirring for 30 min, the clear organic
layer was separated, washed with 100 mL of water, and
evaporated to afford 10.74 g (79.0% based on theory) of
enantiopure (+)-(R)-4 (ee > 99.9% according to HPLC) as
(-)-(S)-SYNPHOS 5: mp > 260 °C. [R]20 ) (-) 44
D
(c ) 0.1, C6H6). 1H NMR (CDCl3): δ ) 3.35 (m, 2H), 3.83
(m, 4H), 4.13 (m, 2H), 6.62 (dd, J ) 8.0, 3.0 Hz, 2H), 6.85
(d, J ) 8.0 Hz, 2H), 7.05-7.10 (m, 4H), 7.20-7.25 (m,
8H), 7.27-7.32 (m, 8H). 31P NMR (CDCl3): δ ) -14.30.
ESI-MS m/z 639 (M + H)+. HRMS: calcd for C40H32O4P2
(M + H) 639.1854; found 639.1844.
(+)-(R)-SYNPHOS 5: mp > 260 °C. [R]20 ) (+) 32
D
(c ) 0.1, CHCl3). All other analytical data were identical to
those of compound (-)-(S)-SYNPHOS 5.
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 1 mL of degassed anhydrous acetone was
added dropwise. A methanolic solution of HBr (122 µL, 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 vessel was placed in
a 500-mL stainless steel autoclave, which was pressurized
at the desired pressure and warmed to the desired temperature
for 24 h. The methanol was concentrated, and the crude
product was filtered on a short pad of silica gel (cyclohexane/
1
AcOEt, 1:1). Conversion and ee were determined by H
NMR and chiral GC.
Multigram-Scale Asymmetric Hydrogenation of Meth-
yl Acetoacetate. In a 0.5-L flask, in situ catalyst “((R)-
SYNPHOS)RuBr2” (77.5 mg, 0.086 mmol) was prepared
according to the previously described typical procedure.
Methyl acetoacetate (100 g, 0.861 mol) and 200 mL of
methanol were degassed and added to the catalyst via cannula
under a flow of argon. The reaction vessel was introduced
in a 600-mL stainless steel autoclave, which was pressurized
at 20 bar and warmed to 50 °C for 3 days. The methanol
was evaporated in vacuo, and the crude product was filtered
on silica gel (cyclohexane/AcOEt, 1:1). (3R)-Methyl hy-
a white solid. [R]20 ) (+) 143 (c ) 1, CHCl3). All other
D
analytical data were identical to those of racemic 4.
The combined filtrates were concentrated under vacuum
and treated as described above (1 N KOH and usual workup).
The resulting white solid (15.5 g) was then treated, similary,
with (D)-(+)-dibenzoyltartaric acid (7.7 g, 21.4 mmol) and
finally 10.64 g (78.2% based on theory) of (-)-(S)-4 (ee >
99.9% according to HPLC) was obtained as a white solid.
[R]20 ) (-) 142 (c ) 1, CHCl3). All other analytical data
D
were identical to those of racemic 4.
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droxybutanoate was obtained as a colorless oil with 91%
yield (92.6 g) and ee > 99% according to GC (Lipodex A,
35 °C, hold for 30 min, ramp to 100 °C at 1 °C/min, retention
time: 45.34 min (S); 48.00 min (R)).
analytical support. We also thank Dr. R. Schmid (Hoffmann-
La Roche) for a generous gift of (S)- and (R)-MeO-BIPHEP.
Received for review January 21, 2003.
OP034016W
Acknowledgment
We thank I. Braccini from Fournier Pharma for her
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