Inversion of enantioselectivity in the hydrogenation of ketopantolactone on platinum modified by ether derivatives of cinchonidine

Article abstract of DOI:10.1016/S0957-4166(03)00528-7

Asymmetric hydrogenation of ketopantolactone was studied on a 5 wt% Pt/Al₂O₃ catalyst in the presence of cinchonidine and its O-methyl, -ethyl, -phenyl and -trimethylsilyl derivatives. Inversion of enantioselectivity with the latter two bulky substituents proved that in the enantiodifferentiating step cinchonidine adsorbs via the quinoline ring lying approximately parallel to the Pt surface. The striking nonlinear effect observed with cinchonidine-O-phenyl-cinchonidine mixtures is attributed to differences in the adsorption strength and geometry of the modifiers.

Full text of DOI:10.1016/S0957-4166(03)00528-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2573–2577
Inversion of enantioselectivity in the hydrogenation of
ketopantolactone on platinum modified by ether derivatives of
cinchonidine
Simon Diezi,a Andras Szabo,b Tamas Mallata and Alfons Baikera,*
aSwiss Federal Institute of Technology, Institute for Chemical and Bioengineering, ETH Ho¨nggerberg, Wolfgang-Pauli-Straße 10,
CH-8093 Zu¨rich, Switzerland
bUbichem Research Ltd, Pusztaszeri ut 59, H-1025 Budapest, Hungary
Received 15 May 2003; accepted 3 July 2003
Abstract—Asymmetric hydrogenation of ketopantolactone was studied on a 5 wt% Pt/Al2O3 catalyst in the presence of
cinchonidine and its O-methyl, -ethyl, -phenyl and -trimethylsilyl derivatives. Inversion of enantioselectivity with the latter two
bulky substituents proved that in the enantiodifferentiating step cinchonidine adsorbs via the quinoline ring lying approximately
parallel to the Pt surface. The striking nonlinear effect observed with cinchonidine–O-phenyl-cinchonidine mixtures is attributed
to differences in the adsorption strength and geometry of the modifiers.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
(Scheme 1).1,2 Various rhodium(I) complexes have been
tested in this reaction3–7 that afforded up to 98.7% ee.8
The enantioselective hydrogenation of ketopantolac-
tone 1 has been extensively investigated as one enan-
tiomer of the product, (R)-(−)-pantolactone 2, is an
intermediate in the synthesis of pantothenic acid (vita-
min B family) and a constituent of coenzyme A
A
heterogeneous catalyst, supported Pt chirally
modified by cinchonidine (CD)9–11 was less selective: the
best ee was only 91.6% to (R)-2.12 Practical advantages
of the latter process are the extremely low CD/1 molar
ratio, only 4 ppm, and the high production rate
achieved in a continuous flow fixed bed reactor (TOF=
1420 h−1).13
Supported by theoretical calculations, we proposed a
model for the reactant–modifier interaction on the Pt
surface involving a H-bond between CD and the half-
hydrogenated state derived from 1 (Fig. 1).10 However,
Scheme 1. Hydrogenation of ketopantolactone 1 to pantolac-
tone 2 over chirally modified Pt/Al2O3 and the structure of
ether derivatives of cinchonidine used as modifiers.
Figure 1. Top view of a calculated model for the CD-1
interaction over the Pt surface, leading upon hydrogenation
to (R)-2.10 The p-bonded quinoline ring of CD and the two
carbonyl groups of 1 lie approximately parallel to Pt.
* Corresponding author. Tel: (+41)1-632-3153; fax: (+41)1-632-1163;
e-mail: baiker@tech.chem.ethz.ch
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00528-7

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S. Diezi et al. / Tetrahedron: Asymmetry 14 (2003) 2573–2577
there is no direct evidence yet for the assumption
implied to the model that 1 and the quinoline ring of
CD are adsorbed parallel to the Pt surface during the
enantiodifferentiating step. Various surface science
techniques (NEXAFS,14 STM,15 XPS,16 LEED,17
of modifiers depended also on the pressure in the range
1–40 bar. The latter two modifiers possess small O-
alkyl groups that do not substantially change the
adsorption geometry, compared to CD. The reasonably
good ee’s achieved in these experiments support the
assumption that the OH function of CD is not involved
in the enantiodifferentiating step (Fig. 1). When using
TMSOCD or PhOCD as modifiers, the opposite enan-
tiomer formed in excess. The most striking effect was
observed in toluene where CD afforded 79% ee to
(R)-2, whereas modification with PhOCD resulted in
52% ee to (S)-2. Decreasing the temperature to 0°C
(under otherwise standard conditions) improved the ee
to 54.4% in the latter reaction.
SERS,18 cyclic voltammetry,19 IR20–22
) and H/D
exchange23,24 clarified some important details of the
adsorption of CD on Pt but none of these methods
allowed a real in situ investigation, i.e. in the presence
of the reactant. ATR-IR studies in H2-saturated
CH2Cl2 revealed three differently adsorbed species of
CD: a p-bonded species, which adsorbed via the aro-
matic ring nearly parallel to the Pt surface and two
species, in which the aromatic ring is tilted relative to
the Pt surface.20,21 The former adsorption geometry
would correspond to the assumption depicted in Figure
1.
Certainly, a complex between modifier and 1, as
depicted in Figure 1, cannot establish in the presence of
the bulky trimethylsilyl and phenyl substituents in
TMSOCD and PhOCD, respectively. In the original
model calculated for the CD-1 interaction, CD is
bound via hydrogen bonding to the half-hydrogenated
state derived from 1.10 Besides, a steric repulsion
exerted by the quinoline ring ensures a fixed adsorption
of 1 with dominantly one enantioface on the Pt surface.
Introduction of the bulky trimethylsilyl or phenyl sub-
stituents changes dramatically the chiral pocket avail-
able for the adsorption of 1 over the Pt surface and
leads to the favored adsorption of 1 on the opposite
enantioface. A plausible explanation may be that
TMSOCD and PhOCD do not adsorb via the quinoline
ring being approximately parallel to the Pt surface
(p-bonding) but rather in a tilted position (N-lone pair
bonding). This change in the adsorption geometry
should result in a considerably weaker adsorption of
these modifiers compared to the adsorption of CD.
Another possibility is that TMSOCD and PhOCD still
adsorb with the quinoline ring approximately parallel
to the Pt surface but the bulky phenyl and trimethylsilyl
groups ‘lying’ on the surface change the adsorption
mode of 1.
Here we used another approach to clarify the adsorp-
tion mode of CD and its interaction with 1 in the
enantiodifferentiating complex: we synthesized some
ether derivatives of CD (Scheme 1) and studied the
influence of bulkiness of the functional group on the
hydrogenation of 1. If CD adsorbs via the quinoline
ring lying approximately parallel to the Pt surface, the
increasing steric hindrance in the ether derivatives
should successively diminish the enantioselectivity,
providing a truly in situ evidence for our model. This
approach led us also to some other interesting observa-
tions, which will be reported below.
2. Catalytic hydrogenations with cinchonidine
derivatives
At first we investigated the hydrogenation of 1 in
toluene and THF over a 5 wt% Pt/Al2O3 catalyst (Fig.
2). In both solvents CD afforded somewhat higher ee’s
to (R)-2 than MeOCD or EtOCD, though the efficiency
3. Nonlinear behavior of modifier mixtures
To estimate the relative adsorption strength of the
modifiers on Pt, the hydrogenation of 1 was carried out
with mixtures of CD and PhOCD. A strong nonlinear
behavior was observed as illustrated in Figure 3. The
‘expected’ or theoretical ee (dashed line) was calculated
assuming that the molar ratios of the modifiers in
solution and on the Pt surface are identical, and the
reaction rates and ee’s are linear combinations of those
measured with CD and PhOCD alone. The average
hydrogenation rates with the modifiers alone were simi-
lar: 183 and 140 mmol/h for CD and PhOCD, respec-
tively. Nontheless, CD controlled the enantioselection
in the whole range studied and even a modifier mixture
containing only 0.7 mol% CD afforded 33% ee to
(R)-2. This nonlinear effect is even more striking when
considering that the purity of commercial CD was only
92% and contained 7% quinidine that alkaloid alone
affords (S)-2 in excess.
Figure 2. Enantioselectivities in the hydrogenation of 1 over a
5 wt% Pt/Al2O3 catalyst with two different solvents (ꢀ
toluene; ꢁ THF) under standard reaction conditions. The
structure of the modifiers is shown in Scheme 1.

S. Diezi et al. / Tetrahedron: Asymmetry 14 (2003) 2573–2577
2575
efficiently compete with CD for the active Pt sites. It is
very likely that some steric effects and electronic inter-
actions also play a role though this contribution cannot
be reliably estimated yet. This type of interactions has
been thoroughly investigated in connection with the
nonlinear effects (ligand association) in homogeneous
catalysis.25,26
4. Conclusions
Hydrogenation of 1 over Pt modified by ether deriva-
tives of CD provides strong support to our structural
model for the enantiodifferentiating diastereomeric
complex proposed earlier (Fig. 1).10 Namely, the OH
group of CD is not involved in the modifier-1 interac-
tion and in the modifier-1 complex CD adsorbs approx-
imately parallel to the metal surface via the quinoline
ring (p-bonding). The hydrogen bonding between the
quinuclidine N and the half-hydrogenated state of 1,
together with the steric hindrance by the quinoline ring,
results in (R)-2 as the dominant product. Replacing the
OH group of CD by a bulky PhO or TMSO group
prevents this adsorption mode of 1 and affords (S)-2 as
the major enantiomer. If the quinoline ring of CD
would adopt a tilted position relative to the Pt surface
during interaction with 1 (compare to Figs. 1 and 4),
replacement of the OH group by the bulky PhO or
TMSO groups should not significantly influence the
adsorption of 1 and thus the stereochemical outcome of
the hydrogenation reaction.
Figure 3. Hydrogenation of 1 over 5 wt% Pt/Al2O3 modified
by CD-PhOCD mixtures; standard reaction conditions in
toluene.
A practically and scientifically important consequence
of the observed strong nonlinear effect is that only
carefully purified cinchona derivatives provide genuine
results concerning enantioselectivity. Trace amounts of
CD can outperform the enantiodifferentiation of its
derivatives, as demonstrated for PhOCD. This behavior
is presumably more general and can be extended to
other types of chiral modifiers in heterogeneous cataly-
sis. Furthermore due care has to be taken when inter-
preting the behaviour of modifier mixtures screened by
high-throughput methods.
Figure 4. Schematic illustration of the adsorption of CD and
PhOCD on an idealized flat Pt surface, showing the consider-
able steric hindrance by the phenyl group. The structure of
PhOCD corresponds to the energetic minimum, as derived
from preliminary calculations using Gaussian 98.
The well-known nonlinear effect has originally been
described for homogeneous catalytic reactions carried
out with enantiomerically impure ligands.25,26 This
interesting phenomenon has recently been extended to
mixtures of two diastereomers and even to two chemi-
cally different chiral ligands in homogeneous cataly-
sis,27–31 and to similar but chemically different modifiers
in heterogeneous catalysis.32–37 The basic requirement
for the extension is that the ligand or modifier pairs
afford products of opposite configuration.
5. Experimental
5.1. Synthesis of O-substituted cinchonidines
Melting points were determined using Bu¨chi-545 auto-
1
matic melting point apparatus. H NMR spectra were
recorded by Varian Unity Inova at 400 MHz in CDCl3.
All reactions were carried out under Ar. Starting mate-
rials were purchased from Aldrich and used without
further purification. DMSO, DMF and THF were
dried over molecular sieves before use.
As mentioned in the introduction, ATR-IR studies of
CD adsorption on Pt20,21 allowed to select conditions
nearest to those of catalytic hydrogenation. Based on
this study we propose that the nonlinear behavior
shown in Figure 3 is due to the different geometry and
strength of the alkaloid modifier adsorption on Pt. CD
adsorbs stronger than PhOCD. The quinoline ring of
CD lying approximately parallel to the surface interacts
strongly with Pt via p-bonding (Fig. 4). In contrast,
PhOCD adopts a tilted position; it is anchored to Pt
only weakly via the aromatic N atom and cannot
5.2. O-Methyl-cinchonidine (MeOCD)
CD (10.0 g, 34 mmol) was added to a stirred suspension
of NaH (2.1 g, 88 mmol) in dry DMF (50 ml) and the
mixture was stirred for 30 min at rt, then 1 h at 50°C.
The solution was cooled below 5°C and iodomethane

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S. Diezi et al. / Tetrahedron: Asymmetry 14 (2003) 2573–2577
(2.2 ml, 15 mmol) was added. After 1 h stirring at
0–5°C the reaction mixture was diluted with water (150
ml) and extracted with EtOAc (2×100 ml). The com-
bined organic layer was extracted with 2 M HCl, the
aqueous solution was washed with hexane (50 ml) and
the pH of the solution was adjusted to alkaline with
solid NaHCO3. After extraction with EtOAc (2×100
ml), the organic layer was dried over Na2SO4 and the
solvent was evaporated to dryness (6.9 g white crystals,
a mixture of MeOCD and starting CD). Pure product
was obtained by chromatography on silica with hex-
ane–acetone–TEA 40:18:1 followed by crystallization
from hexane. Yield: 5.6 g (46%) white crystals. Mp
126.6–126.1°C; NMR (CDCl3) 8.90 (d, 1H), 8.15 (d,
1H), 8.10 (d, 1H) 7.70 (t, 1H), 7.57 (t, 1H), 7.42 (d,
1H), 5.72 (m, 1H), 5.04 (d, 1H), 4.91–4.88 (m, 2H),
3.40–3.30 (m, 1H), 3.28 (s, 3H), 3.10–3.03 (m, 2H),
2.75–2.55 (m, 2H), 2.13–2.10 (m, 1H), 1.80–1.70 (m,
3H), 1.60–1.50 (m, 2H); MS (M+H+) 309.
(1.45 g, 7.5 mmol) were added and stirred for 30 min.
After addition of iodobenzene (0.85 ml, 7.5 mmol) the
mixture was kept at 100°C for 72 h. After cooling to
room temperature, water (25 ml), dichloromethane (50
ml), ethylenediaminetetraacetic acid (0.5 g), and finally
cc. ammonia solution (5 ml) were added. The mixture
was stirred at room temperature for 1 h, the organic
layer was separated, and the aqueous phase was
extracted with CH2Cl2 (2×15 ml). The combined
organic layer was washed with 5% ammonia solution
(5×25 ml) until the aqueous phase remained colorless,
then water (25 ml) and solvent were evaporated in
vacuo and the residue was dissolved in EtOAc (50 ml).
It was extracted with 2 M HCl solution (50 ml), the
acidic solution was washed with EtOAc (2×25 ml).
Then the pH was set to alkaline with solid NaHCO3
and extracted with EtOAc (2×30 ml). The combined
organic layer was washed with brine, dried over
Na2SO4 and evaporated to dryness. Crude product was
purified over silica using hexane–acetone–TEA 40:18:1
as eluent. After evaporation of the solvent the product
was crystallized from hexane (0.6 g, 1.6 mmol, white
5.3. O-Ethyl-cinchonidine (EtOCD)
1
EtOCD was synthesized according to the recipe for
MeOCD, but iodoethane was used instead of
crystals). Yield: 22%; mp 126.3–126.4°C; H NMR (400
MHz, CDCl3): l=8.83 (d, 1H), 8.20 (d, 1H), 8.19 (d,
1H) 7.78 (t, 1H), 7.57 (m, 1H), 7.62 (m, 1H), 7.10 (m,
2H), 6.88 (m, 1H), 6.78 (m, 2H), 6.08 (d, 1H), 5.73 (m,
1H), 4.98–4.82 (m, 2H), 3.40–3.30 (m, 1H), 3.28 (s, 2H),
2.75–2.55 (m, 2H), 2.13–2.10 (m, 1H), 1.80–1.70 (m,
3H), 1.60–1.50 (m, 2H); MS: 371 (M+H+).
1
iodomethane. Yield: 55%, colorless oil. H NMR (400
MHz, CDCl3): l=8.90 (d, 1H), 8.12 and 8.10 (two
overlapping d, 2H) 7.72 (t, 1H), 7.60 (t, 1H), 7.52 (d,
1H), 5.75 (m, 1H), 5.17 (d, 1H), 4.97–4.86 (m, 2H), 3.43
(qa, 2H) and 3.41 (s, 1H), 3.15–3.05 (m, 2H), 2.75–2.57
(m, 2H), 2.30–2.22 (m, 1H), 1.85–1.75 (m, 3H), 1.65–
1.55 (m, 2H), 1.25 (t, 3H); MS: 323 (M+H+).
5.6. Catalytic hydrogenation
5.4. O-Trimethylsilyl-cinchonidine (TMSOCD)
Tetrahydrofuran (THF, 99.5%, J. T. Baker) was dried
over Na before use. Toluene (99.5%, J. T. Baker) and
CD (92%, Fluka; impurities: 1% quinine, 7% quinidine,
determined by HPLC at Fluka) were used as received.
TMSOCD was prepared according to a recent proce-
dure.38 CD (2.0 g, 6.7 mmol) and triethylamine (TEA,
0.81 g, 8.0 mmol) were dissolved in THF. The solution
was cooled to 0–5°C and chlorotrimethylsilane (0.87 g,
8.0 mmol) dissolved in THF was added dropwise. The
reaction mixture was allowed to warm to room temper-
ature and stirred at this temperature overnight, then at
60°C for 2 h. The mixture was poured to ice–water
(ꢀ50 ml) and extracted with dichloromethane (2×50
ml), the combined organic layers were washed with
water and brine, dried over Na2SO4 and evaporated to
dryness. Column chromatography on silica with hex-
ane–acetone–TEA 40:18:1 afforded a white crystalline
material; yield: 1.2 g, 49%; mp 75.8–76.7°C; NMR
(CDCl3) 8.84 (d, 1H), 8.14 and 8.10 (two overlapping d,
2H) 7.71 (t, 1H), 7.56 (t, 1H), 7.48 (d, 1H), 5.71 (m,
1H), 5.60 (d, 1H), 4.92–4.87 (m, 2H), 3.40–3.30 (m,
1H), 3.10–3.00 (m, 2H), 2.75–2.55 (m, 2H), 2.10–2.10
(m, 1H), 1.80–1.70 (m, 3H), 1.60–1.50 (m, 2H), 0.1 (s,
9H); MS (M+H+) 367.
A 5 wt% Pt/Al2O3 catalyst (Engelhard 4759) was prere-
duced in flowing H2 for 60 min at 400°C, cooled to
room temperature in H2 in 30 min, and flushed with
nitrogen. The pretreated catalyst was used on the same
day. Hydrogenations were carried out at room temper-
ature (ca. 20°C) in a stainless steel autoclave equipped
with a 50 ml glass liner and a PTFE cover, and
magnetic stirring (1000 rpm). Total pressure (40 bar)
and hydrogen uptake were controlled by computerized
constant-volume constant-pressure equipment (Bu¨chi
BPC 9901). In a standard procedure, 42 mg catalyst in
5 ml solvent was exposed to flowing H2 for 2 min. Then
6.8 mol modifier or modifier mixture was added in 1 ml
solvent. After a short preadsorption time of 1 min 236
mg (1.84 mmol) ketopantolactone 1 was added and the
reaction was started. Conversion and enantioselectivity
were determined by gas chromatography using a Chi-
rasil-DEX CB column (Chrompack). No other product
beside the two enantiomers of pantolactone 2 could be
detected.
5.5. O-Phenyl-cinchonidine (PhOCD)
This compound was prepared according to the litera-
ture procedure for the synthesis of dihydroquinidyl aryl
ethers.39 CD (2.2 g, 7.5 mmol) was dissolved in anhy-
drous DMSO (30 ml), NaH (0.40 g, 10 mmol) was
added at room temperature and the mixture was stirred
for 1 h. Then abs. pyridine (1.2 ml, 15 mmol) and CuI
Acknowledgements
Financial support by the Swiss National Science Foun-
dation is greatly acknowledged. The authors are grate-

S. Diezi et al. / Tetrahedron: Asymmetry 14 (2003) 2573–2577
2577
ful to A. Vargas for optimization of the structure of
PhOCD.
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