Asymmetric hydrogenation of an α,β-unsaturated ketone by diamine(ether-phosphine)ruthenium(II) complexes and lipase-catalyzed kinetic resolution: A consecutive approach

Article abstract of DOI:10.1016/S0957-4166(03)00129-0

The RuCl₂(η¹-Ph₂PCH₂CH ₂OCH₃)₂(diamine) complexes 2L₁-2L₅ have been prepared in high yields from the reaction of equimolar amounts of RuCl₂(η²-Ph₂PCH₂CH ₂OCH₃)₂ 1 with various kinds of chelating diamines L₁-L₅ to form five-membered chelates with ruthenium. These novel ruthenium(II) complexes have been used as catalysts in the asymmetric hydrogenation of the prochiral ketone trans-4-phenyl-3-butene-2-one 3, using 2-propanol and different types of cocatalysts. Whereas complexes with achiral diamines afforded the racemic alcohols, complexes with chiral diamines (R,R or S,S) allowed the formation of the corresponding enantiomerically enriched secondary alcohol (S or R) with ee values of 45%. In order to obtain the secondary alcohol with ee of >99%, the kinetic resolution of enantiomerically enriched trans-4-phenyl-3-butene-2-ol 3 was performed in a consecutive approach using either the lipase-catalyzed enantioselective transesterification of the alcohol with isopropenyl acetate as the acyl donor in toluene or the enantioselective hydrolysis of the corresponding acetate in buffer. The determination of the enantiomeric excess (ee) of the resulting enantiomerically enriched secondary alcohols was performed by gas chromatography using heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin as the chiral stationary phase.

Full text of DOI:10.1016/S0957-4166(03)00129-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1045–1053
Asymmetric hydrogenation of an a,b-unsaturated ketone by
diamine(ether–phosphine)ruthenium(II) complexes and
lipase-catalyzed kinetic resolution: a consecutive approach
Ekkehard Lindner,a,* Ashraf Ghanem,b Ismail Warad,a Klaus Eichele,a Hermann A. Mayera and
Volker Schurigb
aInstitute of Inorganic Chemistry, University of Tu¨bingen, Auf der Morgenstelle 18, 72076 Tu¨bingen, Germany
bInstitute of Organic Chemistry, University of Tu¨bingen, Auf der Morgenstelle 18, 72076 Tu¨bingen, Germany
Received 5 December 2002; accepted 31 January 2003
Abstract—The RuCl2(h1-Ph2PCH2CH2OCH3)2(diamine) complexes 2L1–2L5 have been prepared in high yields from the reaction
of equimolar amounts of RuCl2(h2-Ph2PCH2CH2OCH3)2 1 with various kinds of chelating diamines L1–L5 to form five-membered
chelates with ruthenium. These novel ruthenium(II) complexes have been used as catalysts in the asymmetric hydrogenation of the
prochiral ketone trans-4-phenyl-3-butene-2-one 3, using 2-propanol and different types of cocatalysts. Whereas complexes with
achiral diamines afforded the racemic alcohols, complexes with chiral diamines (R,R or S,S) allowed the formation of the
corresponding enantiomerically enriched secondary alcohol (S or R) with ee values of 45%. In order to obtain the secondary
alcohol with ee of >99%, the kinetic resolution of enantiomerically enriched trans-4-phenyl-3-butene-2-ol 3 was performed in a
consecutive approach using either the lipase-catalyzed enantioselective transesterification of the alcohol with isopropenyl acetate
as the acyl donor in toluene or the enantioselective hydrolysis of the corresponding acetate in buffer. The determination of the
enantiomeric excess (ee) of the resulting enantiomerically enriched secondary alcohols was performed by gas chromatography
using heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-b-cyclodextrin as the chiral stationary phase. © 2003 Published by
Elsevier Science Ltd.
1. Introduction
Transition metal-catalyzed hydrogenations of carbonyl
groups represent a good method to access secondary
alcohols.1–6,12–16 However, some of the reported pro-
cesses have to be improved for practical purposes due
to their low catalytic activity and low molar substrate/
catalyst ratio. An excellent catalytic performance in the
asymmetric hydrogenation of ketones to secondary
alcohols with 2-propanol as solvent has been reported
using ruthenium(II) complexes attached to C2-symmet-
rical chiral diamines as ligands.2–5,12,17–19 Unfortunately,
the conditions applied, e.g. reaction time of approxi-
mately 15 h or more, and a hydrogen pressure of 8–10
bar, limit their practical use in asymmetric synthesis.
Despite the impressive progress in asymmetric synthe-
sis, catalysis with chiral ruthenium complexes is still
considered to be one of the most fascinating topics in
organic chemistry.1–5 Enantiomerically pure and
enriched secondary alcohols are useful chiral building
blocks for many natural products.6 Accordingly, there
is considerable interest in highly efficient routes to this
class of compounds. They are usually synthesized in
enantiomerically pure form by kinetic resolution of the
racemates using either asymmetric enzymatic
acylation;7 or a dynamic approach based on a lipase/
ruthenium combination8 and the asymmetric reduction
of prochiral ketones which can be performed either
biologically using biocatalytic systems,9 or chemically
via stereoselective reduction using either a catalytic
system10 or a stoichiometric amount of a reducing
agent.11
Recently, ruthenium(II) complexes with ether–phos-
phine and diamine ligands were already successfully
tested in the catalytic hydrogenation of unsaturated
ketones.20 These reactions have been performed under
moderate conditions (35–40°C, low hydrogen pressures
of 2–3 bar), and a molar substrate/catalyst ratio (S/C)
between 1000–4000 resulting in the formation of unsat-
urated secondary alcohols in up to 99% yield. It has to
be emphasized that the hemilabile character of ether–
* Corresponding author. Tel.: +49(0)7071-2972039; fax: +49(0)7071-
295306; e-mail: ekkehard.lindner@uni-tuebingen.de
0957-4166/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0957-4166(03)00129-0

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E. Lindner et al. / Tetrahedron: Asymmetry 14 (2003) 1045–1053
phosphines facilitates the formation of diamine(ether–
phosphine)ruthenium(II) complexes through the pres-
ence of the oxygen donor which is considered to behave
as an intramolecular solvent.21
However, to date, no structural information for a cor-
responding chiral ruthenium(II) complex has been pre-
a structural investigation of
complex 2L4, was performed. The crystal structure is
shown in Figure 1.
sented.20 Therefore,
Herein, we report on the application of the diamine–
bis(ether–phosphine)ruthenium(II) complexes 2L1–2L5
in the selective hydrogenation of an a,b-unsaturated
ketone. Particular interest is directed to complexes with
the chiral diamines L4 and L5, which are able to per-
form the asymmetric hydrogenation of ketones afford-
ing enantiomerically enriched secondary alcohols. In a
consecutive approach, the enantiomerically pure alco-
hol (>99% ee) was obtained by lipase-catalyzed transes-
terification of the enantiomerically enriched secondary
alcohol or lipase-catalyzed hydrolysis of the corre-
sponding acetate.
Complex 2L4 crystallizes with two independent
molecules in the unit cell of the chiral, non-centrosym-
metric monoclinic space group P21. Both molecules 1
and 2 are trans-chloro-cis-phosphine isomers of only
approximate C2 symmetry and differ in the orientation
of the substituents at phosphorus relative to the confor-
mation of the diamine ligand. Common to both
molecules is the regular octahedral coordination geome-
try about ruthenium, only perturbed by the phosphine
groups pushing the chlorine ligands from their axial
positions toward the diamine chelate, as expressed by
the deviation of the ClꢀRuꢀCl angles from linearity,
165.65(7) and 166.34(7)°.20,21 As expected, the phenyl
substituents at the diamine carbon chain favor equato-
rial positions. Because of the fixed R,R-configuration of
the diamine, the chelate ring formation with twist con-
formation results in the predetermined l configuration.
In the case of molecule 2, this twist conformation is
actually slightly distorted toward an envelope confor-
mation with C(75) at the tip: C(75) is displaced from
2. Results and discussion
2.1. Synthesis of the complexes 2L1–2L5 and X-ray
structural determination of 2L4
The synthesis of the diamine–bis(ether–phos-
phine)ruthenium(II) complexes 2L1–2L5 has already
been described in the literature (Scheme 1).20,21
,
the NꢀRuꢀN plane by 0.53 A, while C(76), C(31), and
,
C(32) show smaller deviations in the range 0.27–0.39 A.
Scheme 1. Synthesis of the complexes 2L1–2L5.

E. Lindner et al. / Tetrahedron: Asymmetry 14 (2003) 1045–1053
Table 1. Ruthenium-catalyzed hydrogenation of 3a
1047
Run
Catalyst
Conversion (%)b
H2 (bar)
TOFc
1
2
3
4
5
6
7
8
2L1
2L2
2L3
2L4
2L5
2L4
2L5
2L4
2L5
2L4
2L5
2L4
2L5
90
80
67
3
3
3
2
2
2
2
2.5
2.5
2.5
2.5
2.5
2.5
1120
960
670
1010
1690
1030
1460
480
100
100
100
100
100
100
100
100
100
100
d
d
e
e
9
520
f
10
11
12
13
1880
1990
1090
1500
f
g
g
a Reaction was conducted at 35°C using substrate (S/C=1000, 3–10
g) in 2-propanol (50 ml) [Ru:KOH:substrate] [1:10:1000].
b Yields and selectivities were determined by GC and GCMS analy-
ses.
c TOF: turnover requency (molsub mol−1 h−1).
cat
d [Ru:tKOBu:3] [1:10:1000].
e [Ru:KOH:AgOTf:3] [1:10:5:1000].
f [Ru:KOH:3] [1:40:1000].
g [Ru:KOH:3] [1:10:4000].
and 6 (Scheme 2). Adding to that, it has been reported
that the reduction of 3 can lead to the formation of
(RS)-4 (5 mol%), (RS)-5 (5 mol%), 6 (55 mol%), and
(RS)-7 (45 mol%) in a whole cell bioconversion
process9 (Scheme 2).
All hydrogenations were carried out under mild condi-
tions (2–3 bar hydrogen pressure and 35°C) using sev-
eral cocatalysts (KOH, tBuOK, AgOTf). The results
are summarized in Table 1.
Figure 1. ORTEP plot with atom-numbering scheme showing
the two independent molecules in the crystal structure of 2L4.
Thermal ellipsoids are shown at the 20% probability level,
hydrogen atoms have been omitted for clarity.
The excellent regioselectivity in the hydrogenation of
only the carbonyl group is reminiscent to a stoichiomet-
ric reduction with NaBH4. Turnover frequencies and
conversions decreased when methyl groups were intro-
duced at one carbon atom of the diamine in the com-
plexes 2L1–2L3. This is clearly due to steric effects
(Table 1, runs 1–3). In the case of 2L4 and 2L5 contain-
ing chiral ligands and the substrate 3 the formation of
the enantiomerically enriched alcohol 4 was formed
which was detected as 9 (Scheme 3 and Fig. 2).
2.2. Catalytic activity of the ruthenium(II) complexes
2L1–2L5 in the selective hydrogenation of an a,b-unsat-
urated ketone
The catalytic activity of the ruthenium(II) complexes
2L1–2L5 has been studied in the hydrogenation of
trans-4-phenyl-3-butene-2-one 3. This substrate was
selected as a model, since three different possibilities of
hydrogenation are expected to form (RS)-4, (RS)-5,
Scheme 2. Different possibilities for the hydrogenation of 3.

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E. Lindner et al. / Tetrahedron: Asymmetry 14 (2003) 1045–1053
Scheme 3. Derivatization of (RS)-4 with iPrNCO (carbamate) and (CH3CO)2O (acetate) to achieve a base-line separation in GC.
Figure 2. Gas-chromatographic separation of (RS)-4 derivatized as the acetate (RS)-9 (a), enantiomerically enriched (R)-4 (45%
ee) resulting from the 2L5 catalyst and derivatized as acetate (R)-9 (b), enantiomerically enriched (S)-4 (45% ee) resulting from
the 2L4 catalyst derivatized as acetate (S)-9 (c). Heptakis-(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-b-cyclodextrin was used as
chiral stationary phase. Oven temperature was 130 isothermal for 20 min.
In runs 6 and 7, tKOBu was applied as cocatalyst.
Similar conversions, turnover frequencies and enan-
tioselectivities as in the case of KOH were observed. To
enhance the enantioselectivity of the hydrogenation of
the carbonyl group AgOTf was used (runs 8 and 9).
However, only the turnover frequencies decreased
markedly, while the enantioselectivity was not affected.
The saturated alcohol (RS)-5 was detected only in small
amounts, when the concentration of the cocatalyst
(KOH) was increased (]40 mol) (Table 1, runs 10 and
11).
2.3. Enantioselectivity of the ruthenium(II) complexes
2L1–2L5
The product resulting from the hydrogenation of 3 in
the presence of catalysts 2L4 and 2L5 with (R,R)- and
(S,S)-diamines L4, L5, afforded the alcohols (S)-4 and

E. Lindner et al. / Tetrahedron: Asymmetry 14 (2003) 1045–1053
1049
(R)-4, respectively, with ee values of 45% ([h]2D0 −6.0/+
Four lipases from Pseudomonas cepacia (PSL), Pseu-
domonas cepacia immobilized on diatomaceous earth
(PSL-D), Novozyme 435 (CAL-B) and Lipozyme RM
IM (RML) were screened in resolving the enantiomeri-
cally enriched 4 either in the enantioselective transester-
ification of (S)-4 (45% ee) using isopropenyl acetate as
an acyl donor in toluene in non-aqueous medium or in
the enantioselective hydrolysis of the corresponding
acetate (R)-9, (45% ee) using a phosphate buffer (pH 6)
in aqueous medium. The transesterification of 4 (45%
ee S) was carried out at 40°C in toluene at a molar
ratio of isopropenyl acetate:4 of 2:1 to ensure the
reaction was irreversible (Scheme 4).
6.0) (Figs. 2 and 3)
2.4. Lipase-catalyzed kinetic resolution of the enan-
tiomerically enriched alcohol 4
The use of an enantiomerically enriched alcohol rather
than a racemic one should reduce the time needed to
effect complete resolution.22–25 The kinetic resolution of
4 was performed starting from the enantiomerically
enriched alcohol (R)- or (S)-4 (45% ee) obtained by the
ruthenium-catalyzed asymmetric reduction of 3 with
the aim to reach ꢀ100% ee in a consecutive approach.
Figure 3. Gas-chromatographic separation of the racemic mixture (RS)-4 derivatized as carbamate (RS)-8 (a), enantiomerically
enriched (S)-4 (45% ee) resulting from the 2L4 catalyst and derivatized as carbamate (S)-8 (b), enantiomerically enriched (R)-4
(45% ee) resulting from the 2L5 catalyst and derivatized as carbamate (R)-8 (c). Heptakis-(2,3-di-O-methyl-6-O-tert-
butyldimethylsilyl)-b-cyclodextrin was used as chiral stationary phase. Oven temperature was 130 isothermal for 20 min, 30°C/min
until 160 for 25 min.
Scheme 4. 2L4, 2L5/lipase-catalyzed separation of enriched (RS)-4.

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E. Lindner et al. / Tetrahedron: Asymmetry 14 (2003) 1045–1053
The results of the lipase-catalyzed transesterification of
enriched (RS)-4 are summarized in Table 2.
This is probably due to product inhibition resulting
from the accumulation of products when the conver-
sion is increased in the enzymatic hydrolysis of R
enriched 9, thus competing with the active site of the
enzyme. Adding to that, the acid released from the
enzymatic hydrolysis (Scheme 4) might be involved in
the acylation of the resulting unreacted enantiomeri-
cally pure alcohol (R)-4, thus, increasing the amount of
the racemic ester 9 leading to a decrease in the conver-
sion and enantiomeric excess.
In the transesterification reaction of enantiomerically
enriched 4, (R)-4 was the faster reacting enantiomer
yielding (R)-9 in high ee and leaving (S)-4 unreacted in
enantiomerically pure form. Both lipases from Pseu-
domonas cepacia immobilized on diatomaceous earth
(PSL-D) and CAL-B displayed high enantioselectivity
towards (RS)-4 (Table 2). In regard to the ee of the
remaining substrate (S)-4 and that of the product (R)-9
as well as the rate of conversion (52.1% in 2 h) and
enantiomeric ratio E >200, PSL-D was the best lipase
employed in the transesterification of (RS)-4. PSL-D
was the enzyme of choice applied in the transesterifica-
tion of (RS)-4 using isopropenyl acetate in toluene on a
preparative scale. An E value of 300 was observed and
the reaction was terminated after 3 h yielding (S)-4
with >99% ee and the ester (R)-9 (cf. Scheme 4), which
was recovered with 86% ee determined by capillary GC
CAL-B (Novozyme) not only showed the best perfor-
mance in the analytical runs, but also gave an excellent
result for the hydrolysis of (RS)-9 enriched at a multi-
gram scale (in 24 h, ees 74.5%, eep >99, conv. 43 and E
>300).
3. Conclusion
,
after 50% conversion. 4 A molecular sieves were added
in order to scavenge the liberated acetone formed as a
by-product from the lipase-catalyzed reaction using iso-
propenyl acetate as an acyl donor. The beneficial effect
of molecular sieves was reported previously in the
lipase-catalyzed transesterification of 1-(2-furyl)ethanol
using isopropenyl acetate in organic solvents.7
A set of diamine(ether–phosphine)ruthenium(II) com-
plexes 2L1–2L5 with different diamines L1–L5 were pre-
pared and used as highly active and selective catalysts
in the hydrogenation of 3 under mild conditions. The
complexes 2L4 and 2L5 containing chiral diamine lig-
ands afforded enantiomerically enriched unsaturated
alcohols 4 with 45% ee. Several cocatalysts, e.g. KOH,
tBuOK, AgOTf, were tested in the hydrogenation pro-
cess in the presence of 2L4 and 2L5 at different condi-
tions. A consecutive approach using the ruthenium(II)
complexes 2L4, 2L5 for the enantioselective reduction
and lipase-catalyzed kinetic resolution of the R or S
enriched trans-4-phenyl-3-butene-2-ol 4 (45% ee) was
applied. Four lipases were screened for the transesterifi-
cation/hydrolysis reactions in order to obtain both R
and S enantiomers of the alcohol with >99% ee.
Compared to the transesterification experiments in non-
aqueous medium described above, the enzymatic
hydrolysis of R-enriched 9 proceeded slowly. Only
moderate conversion (45%) but enantioselectivity (up to
99% for the alcohol (R)-4 and 80.8% for the remaining
unreacted ester (S)-9 (Table 3) was achieved after 24 h
using Novozyme IM (CAL-B). In all cases, the hydrol-
ysis reaction was still rapid until 9 h, afterwards, the
reaction proceeded very slowly.
Table 2. Lipase-catalyzed transesterification of scalemic 4 using isopropenyl acetate in toluene (analytical scale)
Lipase
Time (h)
ees (%)a (S)-4
eep (%)b (R)-9
Conversion (%)
Ec
60
230
95
PSL
2
2
4
4
97.2
\99
\99
49.2
86.9
91.8
80.3
52.8
52.1
55.4
33.0
PSL-D
CAL-B
RML
\99
3800
a ees: enantiomeric excess of substrate (S)-4.
b eep: enantiomeric excess of product (R)-9.
c E: ratio ees:eep.
Table 3. Lipase-catalyzed enantioselective hydrolysis of scalemic 9 using phosphate buffer, pH 6 (analytical scale)
Lipase
Time (days)
ees (%)a (S)-9
eep (%)b (R)-4
Conversion (%)
Ec
PSL
2
4
1
4
57.5
30.2
80.8
39.9
\99
\99
\99
\99
36.5
23.2
45.0
28.6
5000
4000
7500
1500
PSL-D
CAL-B
RML
a ees: enantiomeric excess of substrate (S)-9.
b eep: enantiomeric excess of product (R)-4.
c E: ratio ees:eep.

E. Lindner et al. / Tetrahedron: Asymmetry 14 (2003) 1045–1053
1051
4. Experimental
1 h. During the hydrogenation process samples were
taken from the reaction mixture and analyzed by GC.
4.1. General remarks, chemicals and instrumentation
4.3. General procedure for the gram-scale ruthenium-
catalyzed production of enantiomerically enriched 4
The synthesis of the ruthenium(II) complexes was car-
ried out in an inert atmosphere (argon) by using stan-
dard high vacuum and Schlenk-line techniques unless
otherwise noted. Prior to use CH2Cl2, n-hexane, and
Et2O were distilled from CaH2, LiAlH4, and from
sodium/benzophenone, respectively.
Complexes 2L4 and 2L5 (0.018 mmol), respectively,
were placed in a 150 ml Schlenk tube and solid KOH
(0.36 mmol) was added as a cocatalyst. The solid
mixture was stirred and warmed during the evacuation
process to remove oxygen and water. Subsequently the
Schlenk tube was filled with argon and 2-propanol (20
ml) was added. The mixture was vigorously stirred,
degassed by two freeze–thaw cycles, and then sonicated
for 20–40 min (this is important to complete the dis-
solving of the catalyst and cocatalyst). A solution 3
(72.0 mmol) in 2-propanol (60 ml) [Ru:KOH:sub]
[1:20:4000], was subjected to a freeze–thaw cycle in a
different 150 ml Schlenk tube and was added to the
catalyst solution. Finally the reaction mixture was
transferred to a pressure Schlenk tube which was pres-
surized with dihydrogen of 2.5 bar. The reaction mix-
ture was vigorously stirred at 40°C for 3 h. During the
hydrogenation process samples were taken from the
reaction mixture to control the conversion and turnover
frequency. The samples were inserted by a special glass
syringe into a gas chromatograph and the kind of the
reaction products was compared with authentic sam-
ples.
The ether–phosphine ligand Ph2PCH2CH2OCH3 was
prepared according to the literature method.26 The
diamines were purchased from Acros, Fluka, and
Merck and were purified by distillation and recrystal-
lization, respectively. Ph3P and RuCl3·3H2O were avail-
able from Merck and ChemPur respectively, and were
used without further purification. Lipases from Pseu-
domonas cepacia (PSL), Pseudomonas cepacia immobi-
lized on diatomaceous earth (PSL-D) were gifts from
Amano (Nagoya, Japan), Novozyme 435 (an immobi-
lized non-specific lipase, Candida antarctica B, CAL-B,
produced by submerged fermentation of a genetically
modified Aspergillus oryzae microorganism and
adsorbed on a macroporous resin) and Lipozyme RM
IM (RML, an immobilized 1,3-specific lipase from Rhi-
zomucor miehei produced by submerged fermentation
of a genetically modified Aspergillus oryzae microor-
ganism) were gifts from Novo Nordisck A/S Denmark.
The racemic alcohol 3 was synthesized according to a
literature procedure.24 Elemental analyses were carried
out on an Elementar Vario EL analyzer. High-resolu-
4.4. General procedure for the lipase-catalyzed asym-
metric transesterification of enriched (S)-4
1
tion H, 13C{1H}, DEPT 135, and 31P{1H} NMR spec-
tra were recorded on a Bruker DRX 250 spectrometer
All reactants (alcohols, esters) were stored over acti-
vated molecular sieves (4 A) the enantiomerically
1
at 298 K. Frequencies are as follows: H NMR 250.12
,
MHz, 13C{1H} NMR 62.9 MHz, and 31P{1H} NMR
enriched alcohol ((S)-4; 45% ee—74 mg 0.5 mmol,
analytical scale or 8.8 g, 0.06 mol, gram-scale resulting
from the 2L4-catalyzed asymmetric hydrogenation of
trans-4-phenyl-3-butene-2-one 3) and isopropenyl acet-
ate (108.8 mg, 1.0 mmol, analytical scale or 24 g, 0.24
mol, gram-scale) were dissolved in toluene (3 ml analyt-
ical scale or 500 ml gram-scale) in a 5 ml reaction vial
(analytical scale) or 1 L round-bottomed flask (gram-
scale). The reaction mixture was thermostated in an oil
bath to 40°C. A 100 ml sample of the reaction mixture
was withdrawn and derivatized with isopropyl isocya-
nate (10 ml) at 100°C for 30 min, diluted with toluene
(100 ml) and analyzed by GC (t=0 of sample). After-
wards, lipase (100 mg, analytical scale or 3.08 g gram-
scale) was added, followed by the addition of molecular
1
101.25 MHz. Chemical shifts in the H and 13C{1H}
NMR spectra were measured relative to partially
deuterated solvent peaks which are reported relative to
TMS. 31P chemical shifts in the 31P{1H} NMR spectra
were measured relative to 85% H3PO4 (l=0). Mass
spectra: EI-MS; Finnigan TSQ70 (200°C). FAB-MS;
Finnigan 711A (8 kV), modified by AMD and reported
as mass/charge (m/z).
4.2. General procedure for the catalytic studies
The diamine–bis(ether–phosphine)ruthenium(II) com-
plexes 2L1–2L5, (0.026 mmol) were placed into a 150 ml
Schlenk tube and solid KOH (0.26 mmol) was added as
a cocatalyst. The solid mixture was stirred and warmed
during the evacuation process to remove oxygen and
water. Subsequently the Schlenk tube was filled with
argon and 2-propanol (20 ml) was added. The mixture
was vigorously stirred, degassed by two freeze–thaw
cycles, and then sonicated for 20–40 min. A solution of
3 (26 mmol) in 2-propanol (60 ml) was subjected to a
freeze–thaw cycle in a different 150 ml Schlenk tube
and was added to the catalyst solution. Finally the
reaction mixture was transferred to a pressure Schlenk
tube which was pressurized with dihydrogen of 2–3 bar.
The reaction mixture was vigorously stirred at 35°C for
,
sieves 4 A (100 mg analytical scale or 5 g gram-scale).
100 ml samples were taken after several time intervals.
The samples were centrifuged to separate lipase. The
organic layer was treated with isopropyl isocyanate
heated to 100°C for 30 min, then diluted with toluene
(100 ml) and analyzed by GC. The reaction progress
was monitored qualitatively by thin layer chromatogra-
phy using n-hexane/ethyl acetate (9:1 v/v) as eluent. An
aliquot of the supernatant was used for GC analysis.
When maximum conversion was reached (50% after 2
h), the reaction was terminated by filtration. The
enzyme was washed with acetone and then dried in air

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E. Lindner et al. / Tetrahedron: Asymmetry 14 (2003) 1045–1053
for further use. Substrate (S)-4 and product (R)-9 were
separated by flash chromatography over silica gel (n-
hexane/ethyl acetate 9:1) affording 4.1 g ((S)-4) (>99%
ee by GC) [h]D20 −19.9 (c 1, CH2Cl2) [lit. [h]2D0 −24.5 (c
5.16, CHCl3), 98% ee], yield: 47% and 4.3 g ((R)-9)
(87% ee by GC) [h]D20 +74.2 (c 1, CH2Cl2), yield: 49%.
16.4 and 17.0 min, respectively and a separation factor
h=1.08 and resolution Rs=2.83. Upon derivatization
of the racemic alcohol (RS)-4 with isopropyl isocya-
nate, the elution of the carbamate (RS)-8 was in the
reverse order (R)<(S) with 40.8 and 41.2 min, respec-
tively and a separation factor h=1.01 and resolution
Rs=1.07.
4.5. General procedure for the lipase-catalyzed asym-
metric hydrolysis of enriched (R)-9
The substrates 4, 5, 6, and the product 9 were identified
by using a GC/MSD-system HP 6890/5973 (Hewlett–
Packard, Waldbronn, Germany) equipped with an HP
7683 autosampler.
Enzyme (100 mg, analytical scale or 3.15 g of
Novozyme 435, gram-scale) was dissolved in phosphate
buffer (pH 6, 2.8 ml, analytical scale or 250 ml, gram-
scale) and added to the enantiomerically enriched acet-
ate (R)-9 (45% ee R, 0.5 mmol, analytical scale or 7.8 g,
40 mmol, gram-scale resulting from the 2L5-catalyzed
asymmetric reduction of trans-4-phenyl-3-butene-2-one
3) dissolved in toluene (1 ml, analytical scale or 20 ml,
gram-scale) in a 5 ml reaction vial (analytical scale) or
1 L round-bottomed flask (gram-scale). The reaction
mixture was thermostated in an oil bath at 40°C. Then,
100 ml of the reaction mixture (organic layer) was
withdrawn at several time intervals, derivatized with
isopropyl isocyanate, heated to 100°C for 30 min, then
diluted with toluene (100 ml) and analyzed by GC. The
reaction progress was monitored qualitatively by thin
layer chromatography (n-hexane/ethyl acetate 9:1).
When maximum conversion was reached (44% after 24
h), the reaction was terminated by filtration. Substrate
(S)-9 and product (R)-4 were separated by column
chromatography (n-hexane/ethyl acetate 9:1) affording
the 3.3 g (R)-4 (>99% ee by GC) [h]2D0 +19.9 (c 1,
CH2Cl2), yield: 43% and 3.5 g (S)-9 (74.5% ee by GC)
[h]2D0 −71.2 (c 1, CH2Cl2), yield: 46%.
The enantiomeric excess ee of both substrate (ees)
and product (eep) as well as conversion (conv.) and
enantiomeric ratio (E) were determined by the com-
puter program available on the internet http://
www.orgc.TUGraz.at/orgc/programs/selectiv/selectiv.
htm.
5. X-Ray structural analysis of complex 2L4
Crystals of 2L4 were obtained by slow diffusion of
diethyl ether into a dichloromethane solution of 2L4. A
selected crystal was mounted on a Siemens P4 four-cir-
cle diffractometer by using a perfluorinated polyether
(Riedel de Haen) as protecting agent. Graphite-
,
monochromated Mo-Ka radiation (u=0.71073 A) was
used for the measurement of intensity data in the
v-scan mode at a temperature of 173(2) K. Cell
parameters were determined from 50 automatically cen-
tered reflections. The intensity data were corrected for
polarization and Lorentz effects. The structure was
solved by direct methods with SHELXS-86.28a Refine-
ment was carried out by full-matrix least-squares meth-
ods based on F2 in SHELXL-97,28b with anisotropic
thermal parameters for all non-hydrogen atoms.
Hydrogen atoms were included at calculated positions
using a riding model with isotropic temperature factors
equal to 1.2 times the Ueq value of the corresponding
parent atom.
4.6. Enantioselective gas-chromatographic analysis
The enantiomers of the underivatized alcohol (RS)-4
could not be separated on heptakis-(2,3-di-O-methyl-6-
O-tert-butyldimethylsilyl)-b-cyclodextrin used as chiral
stationary phase in GC, however, upon derivatization
with acetic anhydride (the acetate (RS)-9) or isopropyl
isocyanate (the carbamate (RS)-8, cf. Scheme 3) a
base-line separation has been achieved (Figs. 2 and 3).
Thus, the enantioselective analysis of racemic (RS)-4 as
the carbamate (RS)-8 and acetate (RS)-9 were per-
formed simultaneously using a gas chromatograph
Crystallographic details of the structure determination
of 2L4 are summarized below:
Empirical formula C44H50Cl2N2O2P2Ru; Formula
weight 872.77; Crystal system: monoclinic; Space group
(Hewlett–Packard
580,
Waldbronn,
Germany)
equipped with a flame ionization detector (FID). The
chiral stationary phase heptakis-(2,3-di-O-methyl-6-O-
tert-butyldimethylsilyl)-b-cyclodextrin, 20% (w/w) was
dissolved in PS 86 (Gelest, ABCR GmbH & Co.,
Karlsruhe, Germany) and coated on a 25 m×0.25 mm
fused silica capillary column (0.25 mm film thickness)
according to the literature.27 The analytical conditions
were: injector temperature, 200°C; FID temperature,
250°C; oven temperature 130°C for 18 min then 30°C/
min until 160 for 25 min. Hydrogen was used as the
carrier gas (40 KPa column head pressure). The reten-
tion time of (S)-9, (R)-9, (R)-4, (S)-4, were 16.4, 17.0,
40.8, 41.2 min, respectively. Upon derivatization of the
racemic alcohol (RS)-4 with acetic anhydride, the elu-
tion of the acetate (RS)-9 was in the order (S)<(R) with
,
,
,
P21, a (A) 12.136(3), b (A) 29.307(3), c (A) 12.898(3); h
(°) 90, i (°) 114.194(17), k (°) 90; Volume (A )
3
,
4184.7(13) Z 4; Calculated density (g cm−3) 1.385;
Absorption coefficient (mm−1) 0.617; Reflections col-
lected/unique 20134/18465 [R(int)=0.0356]; Data/
restraints/parameters 18465/1/959; Goodness-of-fit on
Fo 1.009; Final R indices [I>2|(I)];a R1=0.0443,
2
Rw(Fo2)=0.0861; R indices (all data).a R1=0.0704,
2
Rw(Fo )=0.0958; Absolute structure parameter 0.01(3);
−3
,
Largest diff. peak and hole (e A ) 0.334 and −0.596.
a
2
2
2 2
R1=%(ꢀꢀFoꢀ−ꢀFcꢀꢀ)/%ꢀFoꢀ; Rw(Fo )={%[w(Fo −Fc ) ]/
2 2
%[w(Fo ) ]}0.5
.

E. Lindner et al. / Tetrahedron: Asymmetry 14 (2003) 1045–1053
1053
The crystallographic data (excluding structure factors)
for the structure in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 190369. These data
can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
9. Hage, A.; Petra, D.; Field, J.; Schipper, D.; Wijnberg, J.;
Kamer, P.; Reek, J.; Leeuwen, P.; Wever, R.; Schoe-
maker, H. Tetrahedron: Asymmetry 2001, 12, 1025–1034.
10. Aitali, M.; Allaoud, S.; Karim, A.; Meliet, C.; Mortreux,
A. Tetrahedron: Asymmetry 2000, 12, 1367–1374.
11. Seyden-Penne, J. Reductions by the Alumino and Borohy-
drides in Organic Synthesis; VCH: New York, 1991.
12. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022.
13. Mu¨ller, D.; Umbricht, G.; Pfaltz, A. Helv. Chim. Acta
1991, 74, 232–236.
14. Genet, J.-P.; Ratovelomanana-Vidal, V.; Pinel, C. Synlett
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15. Gamez, P.; Fache, F.; Mangeney, P.; Lemaire, M. Tetra-
hedron Lett. 1993, 34, 6897–6898.
16. Terhalle, R.; Schulz, E.; Lemaire, M. Synlett 1997, 1257–
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This work was supported by the Fonds der Chemischen
Industrie. A.G. thanks Professor R. D. Schmid (Uni-
versity of Stuttgart) and Professor U. Bornscheuer
(University of Greifswald) for their advice and support
and the Graduate College Analytical Chemistry, Uni-
versity of Tu¨bingen, for a scholarship. I.W. thanks the
Deutsche Forschungsgemeinschaft (Graduate College
Chemistry in Interphases Grant. No. 441/01-2, Bonn-
Bad Godesberg, Germany) for the scholarship and
financial support.
1996, 37, 8165–8168.
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