Multigram-scale asymmetric hydrogenation reactions using Ru-SYNPHOS and Ru-DIFLUORPHOS catalysts

Article abstract of DOI:10.1055/s-2005-918488

The detailed procedure for the synthesis of Ru-SYNPHOS and Ru-DIFLUORPHOS catalysts are described. These catalysts displayed high rates and are quite effective for the large-scale hydrogenation reactions of unsaturated compounds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918488

3
666
PRACTICAL SYNTHETIC PROCEDURES
Multigram-Scale Asymmetric Hydrogenation Reactions Using
®
®
Ru-SYNPHOS and Ru-DIFLUORPHOS Catalysts
a
b
b
a
M
S
ultigram-Sca
é
le
A
symm
v
H
ydrog
e
enations rine Jeulin, Nicolas Champion, Philippe Dellis, Virginie Ratovelomanana-Vidal,*
a
Jean-Pierre Genêt*
a
Laboratoire de Synthèse Sélective Organique et Produits Naturels (UMR 7573 CNRS), Ecole
Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Fax +33(1)44071062; E-mail: jean-pierre-genet@enscp.fr; E-mail: virginie-vidal@enscp.fr
PSP
b
SYNKEM S.A.S., 47 rue de Longvic, BP 50, 21301 Chenôve Cedex, France
Received 16 September 2005
No60
®
®
Abstract: The detailed procedure for the synthesis of Ru-SYNPHOS and Ru-DIFLUORPHOS catalysts are described. These catalysts
displayed high rates and are quite effective for the large-scale hydrogenation reactions of unsaturated compounds.
Key words: ruthenium catalysts, asymmetric catalysis, hydrogenation, ligands, atropisomerism
O
X
O
PPh2
PPh2
X = C2H4 : (S)-SYNPHOS, (S)-1a
X = CF2 : (S)-DIFLUORPHOS, (S)-1b
O
O
X
Procedure 1
RuCl2(p-cymene)]2 (0.5 equiv)
MeOH / CH2Cl2
Procedure 2
[RuCl (p-cymene)]2 (0.5 equiv)
Procedure 3
Ru(COD)(2-methylallyl)2 (1 equiv)
HBr (2 equiv)
[
2
NH Me .HCl (0.75 equiv)
2
2
50 °C, 1.5 h
toluene, 110 °C, 7 h
acetone, 0.5 h, r.t.
Me
H
Me
H
+
Cl–
N
O
O
O
O
Cl
Cl
Ph2
P
Ph2
P
X
X
X
X
X
X
X
X
Cl Cl
Cl
PPh2 Cl
Ru
PPh2
RuBr2
PPh2
O
O
O
O
O
O
O
O
Ru
Ru
PPh2
P
P
Ph2
Ph2
O
O
O
O
in situ
X = C2H4 : (S)-2a
X = CF2 : (S)-2b
X = C2H4 : (S)-3a
X = CF2 : (S)-3b
X = C2H4 : (S)-4a
X = CF2 : (S)-4b
Scheme 1
8
9
Ruthenium(II) complexes incorporating enantiomerically (COD = cycloocta-1,5-diene), Ru(acac) , [RuX (arene)] ,
3
2
2
10
11
pure atropisomeric diphosphines played a crucial role in Ru(RCp)(PPh ) Cl, have emerged in the literature.
3
2
transition-metal catalyzed asymmetric transformations, Notable achievements are based upon ruthenium catalysts
thereby making the design and synthesis of chiral Ru(II)- derived from atropisomeric biaryl-diphosphine ligands1
2,13
1
catalysts an active area of research. The pioneering work which are useful catalysts for the industrial production of
of Noyori et al. led to the discovery of the first mono- fine chemicals.14
nuclear
hexacoordinated
ruthenium
complex
As part as our continuing interest in homogeneous hydro-
2
–4
Ru(O CCH ) (BINAP). Since the initial reports in this
15–17
2
3 2
genation reactions,
we reported general synthetic
5
,6
field, a wide variety of chiral Ru(II)-catalysts isolated
methods for the preparation of chiral ruthenium(II)-cata-
3
7
or prepared in situ from Ru(COD)(h -methylallyl)2
3
7b
lysts such as Ru(P*P)(h -methylallyl) and in situ gener-
2
3
7a,b
ated Ru-catalysts from Ru(COD)(h -methylallyl) ,
2
18
19
[
RuCl (COD)]
and RuCl3 bearing various chiral
2
n
SYNTHESIS 2005, No. 20, pp 3666–3671
x
x.
x
x
.
2
0
0
5
diphosphines. We also described the preparation of a cat-
Advanced online publication: 18.11.2005
DOI: 10.1055/s-2005-918488; Art ID: Z17405SS
Georg Thieme Verlag Stuttgart · New York
ionic monohydride ruthenium complex [Ru{(R,R)-Me-
6
©
DuPHOS}(H)(h -1,3,5-cyclooctatriene)][BF
4
],
which

PRACTICAL SYNTHETIC PROCEDURES
Multigram-Scale Asymmetric Hydrogenations
3667
O
F
F
O
O
O
PPh2
PPh2
O
O
PPh2
PPh2
F
F
O
O
(S)-SYNPHOS : (S)-1a
(S)-DIFLUORPHOS : (S)-1b
Figure 1 (S)-SYNPHOS [(S)-1a] and (S)-DIFLUORPHOS [(S)-1b]
was successfully used for the synthesis of (+)-cis-methyl mechanical stirrer. Hydrogen uptake was monitored to
®
dihydrojasmonate (paradisone ) in an industrial enanti- follow the conversion of the substrate.
oselective hydrogenation process on a multi t/year scale.20
Recently, we designed new atropisomeric diphosphines
O
OH
Ru catalyst
2
1
22
R2
R2
named SYNPHOS and DIFLUORPHOS with relevant
stereoelectronic properties (Figure 1). In this paper, we re-
port the synthetic procedures for the preparation of ruthe-
nium catalysts based upon the SYNPHOS (1a) or
DIFLUORPHOS (1b) ligands and their applications in
multigram-scale asymmetric hydrogenation reactions.
R1
R1
H2
*
MeOH or EtOH
5
–11
12–18
(
multigram scale)
1
2
5,12: R = CH3, R = CO2Et
1
2
6
7
,13: R = Ph, R = CO2Et
1
2
,14: R = CH2OCH2Ph, R = CO2Et
1
2
The chiral Ru(II)-catalysts bearing SYNPHOS or DIFLU-
ORPHOS ligands were prepared on large scale through
3 3
8,15: R = CH , R = COCH
1
2
9,16: R = CH3, R = OH
1
2
2
3
10,17: R = CH2Cl, R = CO2Et
standard procedures involving reaction between each of
1
2
1
1,18: R = CF3, R = CO2Et
the chiral ligand and the precursor complex [RuCl (p-
2
3
cymene)] or Ru(COD)(h -methylallyl) (Scheme 1). The Scheme 2
2
2
isolated
complexes
[Ru(p-cymene){(S)-SYN-
+
–
PHOS}Cl] Cl [(S)-2a] and [Ru(p-cymene){(S)-DIFLU-
Table 1 summarizes our results. The hydrogenation of
ethyl acetoacetate (5) to (S)-12 was first performed with a
complete conversion in ethanol under 20 bar at 50 °C for
+
–
ORPHOS}Cl] Cl
[(S)-2b]
were
conveniently
synthesized quantitatively by mixing respectively the (S)-
SYNPHOS and (S)-DIFLUORPHOS ligands with
4
0 hours by using the in situ generated [RuBr {(S)-SYN-
2
[
RuCl (p-cymene)] in a mixture of MeOH–CH Cl at
2 2 2 2
PHOS}] [(S)-4a] at a high substrate/catalyst ratio (S/
C = 7000) and with excellent enantiofacial discrimination
(Table 1, entry 1, ee = 99.4%).
5
0 °C for 1.5 hours (Scheme 1, Procedure 1). When
[
RuCl (p-cymene)] was treated with SYNPHOS or DIF-
2 2
LUORPHOS in the presence of NH Me ·HCl in toluene at
2
2
Afterwards, most of the reactions were optimized regard-
ing both catalyst loading and reaction times. The in situ
generated [RuBr {(S)-SYNPHOS}] [(S)-4a] catalyst was
also found to be very effective for the hydrogenation of
ethyl 3-oxo-3-phenylpropionate (6) in ethanol allowing
an excellent conversion to (R)-13 (entry 2, 97% conver-
sion) over a very short reaction time of 15 minutes at S/
C = 200 with high level of chiral induction (entry 2,
1
00 °C for 7 hours, large amount of [(RuCl{(S)-SYN-
PHOS}) (m–Cl) ][NH Me ] [(S)-3a] and [(RuCl{(S)-DI-
2
3
2
2
2
FLUORPHOS}) (m–Cl) ][NH Me ] [(S)-3b] catalysts
2
3
2
2
were obtained in 77 and 76% yields, respectively
Scheme 1, Procedure 2). The structure of these Ru-SYN-
(
PHOS [(S)-3a] and Ru-DIFLUORPHOS [(S)-3b]
Ikariya–Mashima’s catalysts were assigned according to
2
3,24
NMR in comparison with literature data.
The in situ
9
8.3% ee) under 4 bar and 80 °C. The cationic Ru-SYN-
PHOS catalytic system [Ru(p-cymene){(R)-SYN-
generated [RuBr {(S)-SYNPHOS}] [(S)-4a] and
2
[
RuBr {(S)-DIFLUORPHOS}] [(S)-4b] were prepared
2
+
–
3
PHOS}Cl] Cl [(R)-2a] ensured very high enantiomeric
excess (entry 3, 98.9% ee) and a complete conversion un-
der a standard set of mild conditions (4 bar, 80 °C, S/
C = 200, 45 min) in ethanol for the hydrogenation reac-
tion of ethyl 4-benzyloxy-3-oxobutyrate (7) to (S)-14,
which is an essential building block for HMG-CoA reduc-
tase inhibitors. Our overall objective was to demonstrate
that the Ru-SYNPHOS complexes could be broadly effec-
tive catalysts for hydrogenations on multigram scale. In
[(RuCl{(R)-SYNPHOS}) (m-
][NH Me ] catalyst (R)-3a induced in methanol the
highly enantio- and diastereoselective 600 mmol-scale
hydrogenation of pentane-2,4-dione (8) to the anti-diol
from a mixture of Ru(COD)(h -methylallyl) and the
diphosphine in acetone by addition of 2.2 equivalents of
2
7
a
HBr according to our convenient procedure (Scheme 1,
Procedure 3). Next, our studies involving the chiral Ru-
SYNPHOS and Ru-DIFLUORPHOS catalysts focused
upon asymmetric catalytic hydrogenation reactions. Once
prepared, these chiral catalysts have been screened for the
synthesis of representative building blocks 12–18
2
6
(
Scheme 2). Most of the chiral alcohols 12–18 have been
this
Cl)
context,
the
2
used as key intermediates for the preparation of target
1
4
3
2
2
molecules in fine chemical production. All the catalytic
tests were carried out in a TOP 45 stainless steel autoclave
which was connected to a 1590 000 TOP INDUSTRIE25
(
S)-15 (entry 4, >99% ee and de) at 20 bar, 50 °C and S/
C = 1000 over 9 hours reaction time. The hydrogenation
parallel hydrogenation system equipped with a central
Synthesis 2005, No. 20, 3666–3671 © Thieme Stuttgart · New York

3
668
S. Jeulin et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Asymmetric Hydrogenations Based upon Ru-SYNPHOS and Ru-DIFLUORPHOS Catalysts
Entry Substrate
Solvent Ru-
H Pressure/ Time S/C
TOF Conv Product
ee
(%)
2
Ratio (h ) (%)a
–
1
Catalyst Temp. (°C) (h)
1
2
O
O
O
5
6
(S)-4a
20 bar/50 40
7000
175 100
800 97
OH
O
(S)-12
(R)-13
99.4
O
O
O
O
EtOH (S)-4a
EtOH (R)-2a
4 bar/80
0.25 200
0.75 200
OH
O
O
98.3
98.9
O
O
O
O
3
O
O
7
4 bar/80
270 100
110 100
OH
(S)-14
BnO
O
BnO
4
5
6
8
9
MeOH (R)-3a
MeOH (S)-4a
20 bar/50
9
1000
2000
1000
OH OH
(R,R)-15 >99b
30 bar/80 40c
–
–
100
100
(S)-16
(S)-17
96
97
O
OH
OH
OH
10 EtOH (R)-3b 100 bar/100 3c
O
O
OH
O
Cl
Cl
O
O
7
O
O
11 EtOH (R)-2b
10 bar/110 0.04 100 2500 100
OH
O
(S)-18
77
F3C
O
F3C
O
a
b
c
1
Conversions were measured by H NMR spectral data of the crude reaction mixture.
De >99% anti.
Reaction time not optimized.
of oxopropanol 9 to (2S)-propane-1,2-diol (16), which is [RuBr {(S)YNPHOS}] [(S)-4a] offered extremely high
2
2
7
a key intermediate in the synthesis of levofloxazine, pro- rates and the highest enantioselectivity (ee = 98.3%) com-
+
–
ceeded smoothly with 96% ee in methanol under 30 bar pared to both [Ru(p-cymene){(S)-SYNPHOS}Cl] Cl
and 80 °C by using the in situ generated [RuBr {(S)-SYN- [(S)-2a] (ee = 91.9%) and [(RuCl{(S)-SYNPHOS}) (m-
2
2
PHOS}] [(S)-4a] at S/C = 2000 (entry 5, 100% conver- Cl) ][NH Me ] [(S)-3a] (ee = 94.2%) allowing a complete
3
2
2
sion). We next endeavored to explore the scope of the Ru- conversion to (R)-13 within 15 minutes at S/C = 200.
DIFLUORPHOS catalysts. Hydrogenation of more chal-
lenging substrates such as ethyl 4-chloro-3-oxobutyrate
(
10) to (S)-17 was performed in ethanol with complete
conversion and high selectivity (entry 6, 97% ee) by using
[
3
(RuCl{(R)-DIFLUORPHOS}) (m-Cl) ][NH Me ] [(R)-
2
3
2
2
b] at high pressure and temperature for 3 hours reaction
time. Finally, when [Ru(p-cymene){(R)-DIFLUOR-
+
–
PHOS}Cl] Cl [(R)-2b] was used, 4,4,4-trifluoro-3-ox-
obutyrate (11) was reduced to (S)-18 with an extremely
short reaction time of only 2 minutes and good selectivity
(
entry 7, 77% ee) in ethanol under 10 bar and 110 °C at S/
C = 100.
Finally, we performed a comparative examination of the
+
–
[
[
Ru(p-cymene){(S)-SYNPHOS}Cl] Cl
[(S)-2a],
(RuCl{(S)-SYNPHOS}) (m–Cl) ][NH Me ] [(S)-3a] and
in situ generated [RuBr {(S)-SYNPHOS}] [(S)-4a] in the
2
3
2
2
2
hydrogenation of ethyl 3-oxo-3-phenylpropionate (6) to Figure 2 Kinetics of hydrogen uptake in asymmetric hydrogenation
(
(
R)-13 under strictly the same reaction conditions of substrate 6 using Ru-SYNPHOS catalysts (S)-2a (ee = 91.9%), (S)-
Figure 2). In this case, the in situ generated
3
a (ee = 94.2%) and (S)-4a (ee = 98.3%).
Synthesis 2005, No. 20, 3666–3671 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Multigram-Scale Asymmetric Hydrogenations
3669
+
–
In conclusion, the Ru(II)-catalysts derived from SYN- [Ru(p-cymene){(S)-DIFLUORPHOS}Cl] Cl [(S)-2b]
Following the typical procedure 1, [RuCl (p-cymene)] (122 mg,
PHOS and DIFLUORPHOS are effective for the hydroge-
nation reaction of a representative range of unsaturated
compounds. The results obtained in this work demonstrat-
ed that high reaction rates and selectivities were achieved
at low catalyst loading on multigram scale by using the
Ru-SYNPHOS and Ru-DIFLUORPHOS catalytic sys-
tems. As far as asymmetric hydrogenation is concerned,
these results confirm that each prochiral substrate requires
an accurate optimization of reaction conditions (pressure,
temperature, reaction time) but also an appropriate choice
of ruthenium catalyst and chiral diphosphine ligand
2
2
0
2
1
.2 mmol) and (S)-DIFLUORPHOS (273 mg, 0.4 mmol) gave (S)-
b as an orange solid (395 mg, ~100%).
H NMR (300 MHz, CDCl ): d = 0.98 (d, J = 6.2 Hz, 3 H), 1.36 (d,
3
J = 6.2 Hz, 3 H), 2.02 (br s, 3 H), 2.95–3.13 (m, 1 H), 3.60–3.79 (m,
1
6
2
H), 4.30–4.52 (m, 1 H), 4.52–4.78 (m, 1 H), 5.95–6.17 (m, 1 H),
.71 (d, J = 8.8 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H), 7.01–8.30 (m,
2 H).
3
1
P NMR (121 MHz, CDCl ): d = 27.5 (d, J = 62 Hz), 42.8 (d,
3
J = 62 Hz).
1
9
F NMR (282 MHz, CDCl ): d = –50.2 (d, J = 91 Hz), –49.4 (d,
3
J = 91 Hz), –48.7 (d, J = 91 Hz), –47.1 (d, J = 91 Hz).
(
SYNPHOS or DIFLUORPHOS), so as to obtain the most
MS (ESI): m/z = 953 ([RuCl(DIFLUORPHOS)(p-cymene)]+).
effective system in terms of catalytic activity and selectiv-
ity.
[
(RuCl{(S)-SYNPHOS}) (m-Cl) ] [NH Me ] [(S)-3a] (Large-
2 3 2 2
Scale Preparation); Typical Procedure 2
1H NMR spectra were recorded at 200 MHz or 300 MHz on a Bruk-
er AC 200 or AC 300 instrument, respectively. Chemical shifts (d)
are expressed in ppm with trimethylsilane (TMS) as external stan-
dard. 31P NMR spectra were recorded at 121 MHz on a Bruker AC
[RuCl (p-cymene)] (7.84 g, 12.8 mmol), (S)-SYNPHOS (16.35 g,
2
2
2
5.6 mmol, 2 equiv) and dimethylamine hydrochloride (1.57 g, 19.2
mmol, 1.5 equiv) were charged in a 500-mL reactor equipped with
a condenser. The system was connected to a supply of vacuum/N2.
Degassed anhyd toluene (250 mL) was added. The mixture was de-
3
8
00 instrument. Chemical shifts (d) are expressed in ppm with an
19
gassed by three vacuum/N cycles at r.t. The mixture was refluxed
5% solution of H PO as external standard. F NMR spectra were
2
3
4
for 7 h and then cooled to r.t. The red-orange suspension was ho-
mogenized by adding degassed CH Cl (200 mL). The dark orange
recorded at 282 MHz on a Bruker AC 300 instrument. Chemical
shifts (d) are expressed in ppm with a 1% solution of trichlorofluo-
2
2
solution was filtered to eliminate excess dimethylamine hydrochlo-
ride crystals. CH Cl was distilled off and orange solids were col-
romethane in CDCl as external standard. GC analyses were per-
3
formed on a Hewlett-Packard 5890 series II instrument connected
to a Merck D-2500 or D-2000 integrator with a flame-ionization de-
tector. Chiral HPLC analyses were conducted on a Waters 600 sys-
tem with Daicel chiral stationary-phase columns.
2
2
lected by filtration of the toluene solution. The solids were dried
under reduced pressure at 45 °C for 18 h to give (S)-3a as an orange-
red powder (16.87 g, 77%).
1
H NMR (300 MHz, CDCl ): d = 2.66 (s, 6 H), 3.89–3.97 (m, 8 H),
Metallic precursor [RuCl (p-cymene)] was purchased from Strem
3
2
2
4
2
6
.08–4.14 (m, 6 H), 4.24–4.28 (m, 2 H), 5.99 (dd, J = 8.7, 10.4 Hz,
H), 6.29 (dd, J = 1.5, 8.7 Hz, 2 H), 6.45 (dd, J = 1.5, 8.6 Hz, 2 H),
.56 (t, J = 1.8, 7.7 Hz, 4 H), 6.88 (t, J = 7.4 Hz, 2 H), 7.00 (td,
Chemicals. [Ru(cycloocta-1,5-diene)(2-methylallyl) ] was synthe-
2
sized from RuCl ·nH O (Strem Chemicals). Toluene and CH Cl
3
2
2
2
were distilled over CaH . Absolute EtOH or MeOH (>99% purity)
2
J = 7.3, 1.6 Hz, 8 H), 7.06–7.27 (m, 14 H), 7.29–7.34 (m, 2 H), 7.48
were used as solvent in the hydrogenation reactions. Hydrogenation
substrates 5, 6 and 8–11 were commercially available. Substrates 5
and 6 were distilled before use. Substrate 7 was synthesized from
commercially available ethyl 4-chloro-3-oxobutyrate (10) using a
reported procedure.26
(
t, J = 8.8 Hz, 4 H), 7.70–7.84 (m, 8 H).
3
1
P NMR (121 MHz, CDCl ): d = 51.1 (d, J = 39 Hz), 52.9 (d,
3
J = 39 Hz). [The complex was obtained with a slight contamination
(8–10%) with an unidentified compound that showed another AB
2
3a
quartet signal at d = 53.7 and 56.6 (J = 42 Hz) ].
+
–
[
RuCl{(S)-SYNPHOS}(p-cymene)] Cl [(S)-2a]; Typical Proce-
dure 1
[(RuCl{(S)-DIFLUORPHOS}) (m–Cl) ][NH Me ] [(S)-3b]
2
3
2
2
[
RuCl (p-cymene)] (122 mg, 0.2 mmol) and of (S)-SYNPHOS
Following the typical procedure 2, (S)-3b was obtained from
[RuCl (p-cymene)] and (S)-DIFLUORPHOS as an orange powder
2
2
(256 mg, 0.4 mmol, 2 equiv) were placed in a 50-mL Schlenk tube
2
2
equipped with a magnetic stirrer bar and a condenser. The system
was connected to a supply of vacuum/argon. The mixture was de-
gassed by three vacuum/argon cycles at r.t. Degassed EtOH (15
mL) and anhyd CH Cl (6 mL) were added to the mixture. The or-
(76%).
1
H NMR (300 MHz, CDCl ): d = 2.67 (s, 6 H), 6.24 (dd, J = 8.8, 9.4
3
Hz, 2 H), 6.50 (d, J = 8.4 Hz, 2 H), 6.64 (d, J = 8.6 Hz, 2 H), 6.58–
2
2
6
.67 (m, 4 H), 6.94 (t, J = 7.6 Hz, 2 H), 7.01–7.35 (m, 24 H), 7.41
ange mixture was refluxed (50 °C) for 1.5 h and then cooled to r.t.
The deep orange solution was filtered through a short pad of Celite
under argon, eluting with degassed EtOH (5 mL) and anhyd CH Cl
(
t, J = 8.6 Hz, 4 H), 7.50 (t, J = 8.5 Hz, 4 H), 7.78 (t, J = 8.4 Hz, 4
H).
2
2
19F NMR (282 MHz, CDCl
J = 95 Hz), –48.4 (d, J = 95 Hz), –45.7 (d, J = 95 Hz).
31P NMR (121 MHz, CDCl
): d = 51.6 (d, J = 38 Hz), 52.1 (d,
3
J = 38 Hz). [The complex was obtained with a slight contamination
(9%) with an unidentified compound that showed another AB quar-
tet signal at d = 53.5 and 56.2 (J = 41 Hz) ].
): d = –51.0 (d, J = 95 Hz), –49.5 (d,
(
5 mL). The solvents were evaporated under vacuum to give (S)-2a
3
as an orange solid (378 mg, ~100%).
1
H NMR (300 MHz, CDCl ): d = 0.98 (d, J = 6.8 Hz, 3 H), 1.35 (d,
3
J = 6.9 Hz, 3 H), 1.99 (s, 3 H), 3.04 (sept, J = 6.8 Hz, 1 H), 3.78–
3
(
6
(
.90 (m, 4 H), 3.96–4.06 (m, 4 H), 4.27 (d, J = 6.7 Hz, 1 H), 4.44
m, 1 H), 5.92 (d, J = 7.0 Hz, 1 H), 6.45 (dd, J = 1.7, 8.8 Hz, 1 H),
.57 (dd, J = 2.0, 8.6 Hz, 1H), 6.85 (dd, J = 8.8, 10.5 Hz, 1 H), 6.94
dd, J = 8.6, 10.3 Hz, 1 H), 7.02 (d, J = 6.8 Hz, 1 H), 7.20–7.33 (m,
2
3a
In situ Generated [RuBr
Procedure 3
A dry 10-mL Schlenk tube was equipped with a magnetic stirrer bar,
a stopper and connected to a supply of vacuum/argon. The flask was
charged with [Ru(cycloocta-1,5-diene)(2-methylallyl) ] (3.2 mg,
{(S)-SYNPHOS}] [(S)-4a]; Typical
2
4
7
H), 7.35–7.54 (m, 8 H), 7.63–7.71 (m, 4 H), 7.76–7.80 (m, 2 H),
.85–8.00 (m, 2 H).
3
1
P NMR (121 MHz, CDCl ): d = 26.1 (d, J = 63 Hz), 40.7 (d,
3
2
J = 63 Hz)
0
.01 mmol) and of (S)-SYNPHOS (6.9 mg, 0.011 mmol, 1.1 equiv),
MS (ESI): m/z = 909 ([RuCl(SYNPHOS)(p-cymene)]+).
then evacuated and filled with argon. Degassed anhyd acetone (1
mL) was introduced via syringe under a stream of argon. Methanol-
Synthesis 2005, No. 20, 3666–3671 © Thieme Stuttgart · New York

3
670
S. Jeulin et al.
PRACTICAL SYNTHETIC PROCEDURES
–
1
1
ic HBr (122 mL, 0.18 mol·L , 2.2 equiv) was added dropwise to the
solution. The mixture was degassed with three vacuum/argon cycles
and stirred for 30 min at r.t. under a stream of argon. The orange
precipitate was concentrated under vacuum. The crude orange-
brown solid (S)-4a was used as catalyst in the hydrogenation reac-
tion without further purification.
H NMR (300 MHz, CDCl ): d = 1.22 (d, J = 6.2 Hz, 3 H), 1.27 (t,
3
J = 7.1 Hz, 3 H), 2.40 (dd, J = 8.4, 16.5 Hz, 1 H), 2.49 (dd, J = 3.7,
16.5 Hz, 1 H), 3.00 (br s, 1 H), 4.17 (q, J = 7.1 Hz, 2 H), 4.13–4.20
(m, 1 H).
(3R)-Ethyl 3-Hydroxy-3-phenylpropionate [(R)-13]
Prepared from ethyl 3-oxo-3-phenylpropionate (6; 1.9 g, 10 mmol)
according to the general hydrogenation procedure, using the in situ
generated Ru/SYNPHOS catalyst (S)-4a (0.05 mmol, prepared ac-
cording to procedure 3) in EtOH (8 mL). Complete conversion was
observed as no other product was detected by NMR. After distilla-
tion of the solvent under reduced pressure, the crude product was
purified by silica gel chromatography (cyclohexane–EtOAc, 8:2),
affording (R)-13 as a colorless oil (0.72 g, 90%). Enantiomeric ex-
cess was measured by chiral HPLC (ee = 98.3%). The reaction was
also carried out on 330 g (1683 mmol) of ethyl 3-oxo-3-phenylpro-
pionate using the in situ generated Ru/SYNPHOS catalyst (S)-4a
with S/C = 500 under 20 bar and 80 °C for 12 h affording (R)-13
(274 g, 84%, 97% ee).
[
RuBr {(S)-DIFLUORPHOS}] [(S)-4b]
2
Following the typical procedure 3, [Ru(cycloocta-1,5-diene)(2-me-
thylallyl) ] (3.2 mg, 0.01 mmol), (S)-DIFLUORPHOS (7.5 mg,
0
crude (S)-4b as an orange solid, which was used as catalyst in the
hydrogenation reaction without further purification.
2
–
1
.011 mmol) and methanolic HBr (122 mL, 0.18 mol·L ) afforded
Asymmetric Hydrogenation on Multigram Scale; (2R,4R)-Pen-
tanediol [(R,R)-15]; Typical Procedure
Pentane-2,4-dione (8; 58 g, 580 mmol) and MeOH (90 mL) were in-
troduced in a 500-mL round-bottomed flask equipped with a mag-
netic stirrer. The system was connected to a supply of vacuum/
argon and the solution was carefully degassed by three vacuum/ar-
Chiral HPLC: Chiralcel OD-H column; eluent: hexane–i-
gon cycles. Solid catalyst [(RuCl{(R)-SYNPHOS}) (m-
Cl) ][NH Me ] [(R)-3a; 496 mg, 0.29 mmol] was added in one por-
2
PrOH (95:5); flow: 1.0 mL/min; l = 254 nm; t = 11.9 min (S) and
R
3
2
2
1
3.9 min (R).
tion. The orange solution was degassed by another vacuum/argon
cycle. Under a flow of argon, the solution was introduced via can-
nula in a 500 mL stainless steel autoclave which was connected to
a 1 590 000 TOP INDUSTRIE parallel hydrogenation system
equipped with a central mechanical stirrer and a gas consumption
control and display system (TOP VIEW software). The atmosphere
of the autoclave was purged three times with argon (8 bar) and twice
with H (5 bar). The temperature of the autoclave was adjusted to
5
was then filled with H (20 bar, stirring 200 rpm). The stirring rate
was adjusted to 1200 rpm and the H uptake was monitored. After
1
H NMR (300 MHz, CDCl ): d = 1.25 (t, 7.1 Hz, 3 H), 2.68 (dd,
3
J = 4.3, 16.2 Hz, 1 H), 2.76 (dd, J = 8.4, 16.3 Hz, 1 H), 4.17 (q,
J = 7.1 Hz, 2 H), 5.12 (dd, J = 4.4, 8.5 Hz, 1 H), 7.25–7.40 (m, 5 H).
2
5
(
3S)-Ethyl 4-Benzyloxy-3-hydroxybutyrate [(S)-14]
Prepared from ethyl 4-benzyloxy-3-oxo-butyrate (7; 5.1 g, 21.4
mmol) according to the general hydrogenation procedure, using Ru/
SYNPHOS catalyst (R)-2a (101 mg, 0.107 mmol) in EtOH (20 mL).
After distillation of the solvent under reduced pressure, the crude
product was purified by silica gel chromatography (cyclohexane–
EtOAc, 8:2), affording (S)-14 as a colorless oil (4.4 g, 85%). Enan-
tiomeric excess was measured by chiral HPLC (ee = 98.9%).
2
0 °C under a H pressure of 1 bar (stirring 200 rpm). The autoclave
2
2
2
total conversion of the substrate (end of H uptake), the autoclave
2
was adjusted to r.t. and atmospheric pressure and finally purged
three times with argon (8 bar, stirring 200 rpm). The contents were
drained off and the autoclave was rinsed with MeOH (20 mL). The
MeOH was distilled off in vacuo to give a brown solid residue
which was triturated in refluxing EtOAc (100 mL) and pentane (50
mL). The suspension was filtered to give pale yellow solids which
were dried under reduced pressure for 18 h to give (2R,4R)-pentane-
Chiral HPLC: Chiralcel OD-H column; eluent: hexane–i-
PrOH (90:10); flow: 0.8 mL/min; l = 215 nm; t : 13.1 min (S) and
R
1
4.8 min (R).
1
H NMR (300 MHz, CDCl ): d = 1.26 (t, J = 7.1 Hz, 3 H), 2.54 (d,
3
J = 6.3 Hz, 2 H), 2.94 (br s, 1 H), 3.48 (dd, J = 5.9, 9.6 Hz, 1 H),
3
.52 (dd, J = 4.6, 9.6 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 4.22–4.26
2
,4-diol [(R,R)-15] (55 g, 90%, de >99% anti, ee >99%).
(m, 1 H), 4.57 (s, 2 H), 7.28–7.27 (m, 5 H).
1
H NMR (300 MHz, CDCl ): d = 1.25 (d, J = 6.3 Hz, 6 H), 1.62 (t,
3
J = 5.6 Hz, 2 H), 2.82 (s, 2 H, OH), 4.18 (m, 2 H).
(
2S)-Propane-1,2-diol [(S)-16]
Enantiomeric and diastereomeric excesses were determined by 19
NMR of the (S)-MTPA ester of (R,R)-15 and achiral gas chromatog-
raphy.
Prepared from hydroxyacetone (9; 1.5 g, 20 mmol) according to the
general hydrogenation procedure, using the in situ generated Ru/
SYNPHOS catalyst (S)-4a (0.107 mmol, prepared according to pro-
cedure 3) in MeOH (1 mL). The solvent was removed under re-
duced pressure and the crude product was purified by distillation
affording (S)-16 as a colorless oil (1.37 g, 89%). Enantiomeric ex-
cess was measured by chiral GC (ee = 96.0%). The same reaction
was carried out on 100 g (1351 mmol) of hydroxyacetone using the
in situ generated Ru/SYNPHOS catalyst (S)-4a with S/C = 2000 un-
der 30 bar at 50 °C for 12 h affording (S)-16 (89.6 g, 87%, 96% ee).
F
(
S)-MTPA Ester of (R,R)-15
1
9
F NMR (282 MHz, CDCl ): d = –71.91 (syn), –71.72 (S,S), –71.64
3
(
R,R).
Achiral GC: DB1701 column, flow: 1.0 mL/min (He), 200 °C (10
min), 5 °C/min, final temperature: 250 °C, t = 18.3 min (R,R), 18.7
min (S,S), 19.7 min (syn).
R
Chiral GC: Chirasil-DEX CB column; temp: 90 °C; t = 3.8 min (S)
R
and 3.9 min (R).
(
3S)-Ethyl 3-Hydroxybutyrate [(S)-12]
Prepared from ethyl acetoacetate (5; 9.1 g, 70 mmol) according to
the general hydrogenation procedure, using the in situ generated
Ru/SYNPHOS catalyst (S)-4a (0.01 mmol, prepared according to
procedure 3) in EtOH (10 mL). After distillation of the solvent un-
der reduced pressure, the crude product was purified by silica gel
chromatography (cyclohexane–EtOAc, 8:2), affording (S)-12 as a
colorless oil (7.6 g, 83%). Enantiomeric excess was measured by
chiral HPLC (ee = 99.4%).
1
H NMR (200 MHz, CDCl ): d = 1.14 (d, J = 9.6 Hz, 3 H), 3.00 (br
3
s, 2 H), 3.37 (dd, J = 7.8 Hz, 11.1 Hz, 1 H), 3.60 (dd, J = 2.9, 11.2
Hz, 1 H), 3.82–3.98 (m, 1 H).
(
3S)-Ethyl 4-Chloro-3-hydroxybutyrate [(S)-17]
Prepared from ethyl 4-chloro-3-oxobutyrate (10; 0.82 g, 5 mmol)
according to the general hydrogenation procedure, using Ru-DIF-
–3
LUORPHOS catalyst (R)-3b (4.4 mg, 2.5 × 10 mmol) in EtOH
(1.8 mL). Complete conversion was observed, as no other product
Chiral HPLC: Chiralcel OD-H column; eluent: hexane–i-PrOH
(
(
was detected by NMR. After distillation of the solvent under re-
duced pressure, the crude product was purified by silica gel chroma-
95:5); flow: 1.0 mL/min; l = 215 nm; t = 7.3 min (R) and 9.2 min
R
S).
Synthesis 2005, No. 20, 3666–3671 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Multigram-Scale Asymmetric Hydrogenations
3671
tography (cyclohexane–EtOAc, 7:3), affording (S)-17 as a colorless
oil. Enantiomeric excess was measured by chiral GC (ee = 97.0%).
(9) Mashima, K.; Kusano, K. H.; Ohta, T.; Noyori, R.; Takaya,
H. J. Chem. Soc., Chem. Commun. 1989, 1208.
(
(
10) Hoke, J. B.; Hollis, L. S.; Stern, E. W. J. Organomet. Chem.
Chiral GC: Lipodex A column; flow: 0.5 mL/min (He); temp:
1993, 455, 193.
7
0 °C; t = 74.5 min (S) and 77.8 min (R).
R
11) Akotsi, O. M.; Metera, K.; Reid, R. D.; McDonald, R.;
Bergens, S. H. Chirality 2000, 12, 514; and references cited
therein.
1
H NMR (300 MHz, CDCl ): d = 1.26 (t, J = 7.1 Hz, 3 H), 2.56 (dd,
3
J = 7.5, 16.4 Hz, 1 H), 2.64 (dd, J = 4.8, 16.4 Hz, 1 H), 3.58 (dd,
J = 1.2, 5,5 Hz, 2 H), 4.15 (q, J = 7.1 Hz, 2 H), 4.20–4.28 (m, 1 H).
(
(
(
12) (a) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029.
(
b) McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809.
13) Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61,
405.
(
3S)-Ethyl 4,4,4-Trifluoro-3-hydoxybutyrate [(S)-18]
Prepared from ethyl 4,4,4-trifluoro-3-oxobutyrate (11; 0.37 g, 2
mmol) according to the general hydrogenation procedure, using Ru/
DIFLUORPHOS catalyst (R)-2b (19.7 mg, 0.02 mmol) in EtOH (4
mL). Complete conversion was observed, as no other product was
detected by NMR. After distillation of the solvent under reduced
pressure, the crude product was purified by silica gel chromatogra-
phy (cyclohexane–EtOAc, 7:3), affording (S)-18 as a colorless oil.
Enantiomeric excess was measured by chiral HPLC (ee = 77.0%).
5
14) (a) Blaser, H. U.; Spindler, F.; Thommen, F. In Handbook
of Homogeneous Hydrogenation; De Vries, J. G.; Elsevier,
C. J., Eds.; Wiley-VCH: Weinheim, 2005, ; in press.
(
b) Blaser, H. U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner,
H.; Studer, M. Adv. Synth. Catal. 2003, 345, 103.
c) Kumobayashi, H.; Miura, T.; Sayo, N.; Saito, T.; Zhang,
(
X. Synlett 2001, 1055.
(
15) (a) Genêt, J.-P. Acc. Chem. Res. 2003, 36, 908. (b) Genêt,
J.-P. In Reductions in Organic Synthesis, ACS Symposium
Series, Vol. 641; Abdel Magid, A. F., Ed.; American
Chemical Society: Washington D. C., 1996, 31.
16) (a) Ratovelomanana-Vidal, V.; Genêt, J.-P. Can. J. Chem.
Chiral HPLC: Chiralpak AD column; eluent: hexane–i-
PrOH (98:2); flow: 1.0 mL/min; l = 215 nm, t = 11.6 min (S) and
R
1
4.4 min (R).
1
H NMR (300 MHz, CDCl ): d = 1.29 (t, J = 7.1 Hz, 3 H), 1.53 (br
3
(
(
s, 1 H), 2.66 (dd, J = 7.3, 16.8 Hz, 1 H), 2.73 (dd, J = 3.1, 16.8 Hz,
2
000, 78, 846. (b) Ratovelomanana-Vidal, V.; Genêt, J.-P.
1
H), 4.21 (q, J = 7.1 Hz, 2 H), 4.38–4.53 (m, 1 H).
J. Organomet. Chem. 1998, 567, 163.
17) Genêt, J.-P.; Pinel, C.; Ratovelomanana-Vidal, V.; Mallart,
S.; Pfister, X.; Bischoff, L.; Caño de Andrade, M. C.; Darses,
S.; Galopin, C.; Laffitte, J. A. Tetrahedron: Asymmetry
1994, 5, 675.
Acknowledgment
This work was partially supported by a grant from the CPER (2000–
2
006 action 10040 ‘Pole Chimie du vivant’). We thank Synkem
(18) Guerreiro, P.; Cano de Andrade, M. C.; Henry, J. C.;
Tranchier, J. P.; Phansavath, P.; Ratovelomanana-Vidal, V.;
Genêt, J. P.; Homri, T.; Touati, A. R.; Ben Hassine, B. C. R.
Acad. Sci., Ser. IIc 1999, 175.
S.A.S. for a grant to S.J.
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(
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(
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Synthesis 2005, No. 20, 3666–3671 © Thieme Stuttgart · New York