Synthesis of chiral catalyst modifiers by hydrosilylation of cinchonidine and their application in the hydrogenation of 1-phenylpropane-1,2-dione and ethyl pyruvate on a supported Pt/Al2O3 catalyst

Article abstract of DOI:10.1002/ejoc.200500161

Four new chiral modifiers were synthesized in order to investigate the effect of distal modifier substitution in the hydrogenation of ethyl pyruvate and 1-phenylpropane-1,2-dione on a supported Pt/Al₂O₃ catalyst. The chiral modifiers

Full text of DOI:10.1002/ejoc.200500161

FULL PAPER
Synthesis of Chiral Catalyst Modifiers by Hydrosilylation of Cinchonidine and
Their Application in the Hydrogenation of 1-Phenylpropane-1,2-dione and
Ethyl Pyruvate on a Supported Pt/Al2O3 Catalyst
Igor Busygin,[a] Esa Toukoniitty,[b] Reijo Sillanpää,[c] Dmitry Yu. Murzin,[b] and
Reko Leino*[a]
Keywords: Heterogeneous catalysis / Hydrogenation / Cinchonidine / Hydrosilylation / Platinum
Four new chiral modifiers were synthesized in order to inves-
(ee = 62–73%), which, however, were slightly lower than the
tigate the effect of distal modifier substitution in the hydro- ee obtained with cinchonidine as the chiral catalyst modifier
genation of ethyl pyruvate and 1-phenylpropane-1,2-dione
on a supported Pt/Al2O3 catalyst. The chiral modifiers were
prepared in good to moderate overall yields by Pt-catalyzed
hydrosilylation of 9-O-TMS-protected cinchonidine with tri-
ethylsilane, triphenylsilane, bis(dimethylsilyl)ethane and (+)-
(R)-methyl(1-naphthyl)phenylsilane followed by cleavage of
the silyl ether protective group. Comparison of the synthe-
sized modifiers in enantioselective hydrogenation using cin-
chonidine as reference modifier is reported, as well as details
on their synthesis and characterization. The X-ray crystal
structure of the 11-(triphenylsilyl)-substituted cinchonidine
analogue has been determined showing that this compound
crystallizes in the open(3)-like conformation observed earlier
for (–)-cinchonidine. In the hydrogenation of ethyl pyruvate,
the new modifiers induced notable enantiomeric excesses
(ee = 84%). The rate for the racemic reaction in the absence
of a chiral modifier was up to threefold higher than the reac-
tion rate with the distally substituted modifiers whereas with
cinchonidine the reaction rate was close to that of the race-
mic hydrogenation. In the hydrogenation of 1-phenylpro-
pane-1,2-dione, 11-(triethylsilyl)-10,11-dihydrocinchonidine
induced an ee of 70% at 50% reactant conversion which was
notably higher than the ee obtained with cinchonidine
(55%). The dependence of enantiomeric excess on the modi-
fier structure is clearly different in the two cases (ethyl pyr-
uvate vs. 1-phenylpropane-1,2-dione) indicating notable dif-
ferences in the enantiodifferentiating mechanisms in these
two model reactions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
heterogeneous nature of the catalyst system, by the fact that
even very small changes in the modifier structure[6] and
concentration,[7] achiral additives present,[8] catalyst pre-
treatment procedure,[9] metal particle size and dispersion,[10]
nature of the solvent[7c,8a,11] and the support material,[12] as
well as the hydrogen partial pressure or surface concentra-
tion[13] affect the catalyst activity and enantioselectivity.
The cinchona-modified Pt catalysts commonly display a
very high substrate specificity and as recently demonstrated
by the extensive studies of Blaser, Baiker and co-workers,[6]
for each substrate, the optimum chiral modifier varies. Cer-
tain qualitative trends have, however, been reported for cat-
alyst systems modified by cinchona alkaloids and related
compounds:[6] 1) an extended π-system, such as quinoline
or naphthalene, is required for efficient adsorption of the
modifier on the metal surface; 2) for inducing sufficient en-
antiocontrol, a chiral amino functionality is needed for sub-
strate–modifier interaction; 3) the sense of asymmetric in-
duction is in most cases controlled by the absolute configu-
ration at the C-8 and C-9 atoms of the cinchona alkaloid.
Substituent effects in the quinuclidine part and more distal
positions of the modifier are considerably less investigated
being the subject of the present investigation.
Introduction
Chiral modification of solid catalysts is one of the most
promising approaches to heterogeneous enantioselective ca-
talysis.[1] Of particular interest are supported Pt catalysts
modified with cinchona alkaloids employed in a range of
enantioselective hydrogenation reactions.[2] With these sys-
tems, enantioselectivities approaching ee = 99% have been
obtained e.g., in the hydrogenation of ethyl benzoylformate
on dihydrocinchonidine-modified Pt/Al2O3 catalyst.[3] Nu-
merous investigations have been aimed at the elucidation of
the operating mechanisms and the origin of enantio-
selectivity in these systems, yet, the exact nature of the sur-
face–modifier–substrate interactions remain under dis-
pute.[4,5] Mechanistical studies are hampered, besides by the
[a] Department of Organic Chemistry Åbo Akademi University,
20500 Åbo, Finland
Fax: +358-2-2154866
E-mail: reko.leino@abo.fi
[b] Laboratory of Industrial Chemistry, Process Chemistry Centre
Åbo Akademi University,
20500 Åbo, Finland
[c] Department of Chemistry, University of Jyväskylä,
40351 Jyväskylä, Finland
Eur. J. Org. Chem. 2005, 2811–2821
DOI: 10.1002/ejoc.200500161
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I. Busygin, E. Toukoniitty, R. Sillanpää, D. Yu. Murzin, R. Leino
FULL PAPER
In previous reports, we have investigated in detail the of other synthetically important enantioselective reactions
enantioselective hydrogenation of a prochiral diketone, 1- and transformations.[18] Here, as a continuation of the pre-
phenylpropane-1,2-dione (A), on cinchona alkaloid modi- vious study, we present a more detailed account on the
fied Pt catalysts (Scheme 1).[14] Under optimal conditions, hydrosilylation of cinchonidine for preparation of new dis-
the main product, (–)-(R)-1-hydroxy-1-phenylpropan-2-one tally substituted chiral catalyst modifiers and report their
(B), has been obtained in 65% ee using cinchonidine as the application in the hydrogenation of 1-phenylpropane-1,2-di-
chiral catalyst modifier. The chiral hydroxy ketone B (also one and ethyl pyruvate.
known as PAC = phenylacetylcarbinol) is an important in-
termediate for the synthesis of ephedrines and pseudoe-
phedrines, which are major ingredients in several pharma-
ceuticals used as anti-asthmatics, vasoconstricting agents
and nasal decongestants.[15] Similar compounds are also
widely utilized as building blocks for the synthesis of other
biologically active compounds including antifungals against
AIDS-related diseases and complications.[16]
Results and Discussion
Synthesis of the Chiral Modifiers
Synthesis of the new chiral modifiers is summarized in
Scheme 2 with modifier structures illustrated in Figure 1.
As described previously,[17] in the first step, cinchonidine (1)
is treated with chlorotrimethylsilane/TEA in THF to pro-
vide 9-O-(trimethylsilyl)cinchonidine (2) as a fairly pure so-
lid in admixture with approximately 10% 9-O-(trimethylsi-
lyl)-10,11-dihydrocinchonidine in 96% yield. The concomi-
tant formation of the dihydrocinchonidine analogue of 2
results from the 10,11-dihydrocinchonidine impurity in
commercial cinchonidine. Next, the TMS-protected cin-
chonidine was hydrosilylated using four commercially avail-
able or readily prepared trialkyl/arylsilanes: 1) triethylsilane,
2) triphenylsilane, 3) bis(dimethylsilyl)ethane and, 4) the
optically active, chiral-at-silicon (+)-(R)-methyl(1-naph-
thyl)phenylsilane in toluene solution in the presence of Kar-
stedt’s catalyst. By this procedure, the 9-O-TMS-protected
11-silyl-substituted dihydrocinchonidines 3a–d were ob-
tained in 38–83% yields after purification by flash column
chromatography. The lowest isolated yield obtained for the
chiral-at-silicon compound 3c is a result of the application
of two subsequent flash-chromatography procedures re-
quired for separation of this compound from the starting
material, due to their similar retention factor values (Rf).
Scheme 1. Hydrogenation of 1-phenylpropane-1,2-dione.
Recently, we observed a significant enhancement of
enantioselectivity in the hydrogenation of A on chirally
modified Pt/Al2O3 in ethyl acetate by use of a distally modi-
fied cinchonidine analogue, 11-(triethoxysilyl)-10,11-dihy-
drocinchonidine, as the chiral catalyst modifier (ee = 70%
vs. 56% obtained with cinchonidine).[17] In the prior investi-
gation, the role of the bulky silyl substituent attached to
the distal part of the quinuclidine moiety of cinchonidine
remained ambigious, although it was shown by Hartree–
Fock calculations that its influence on the conformational
energetics are likely to be minor. The previous investigation
raised the following questions: 1) What is the effect of vary-
ing the distal moiety of the cinchona alkaloid modifier on
enantioselectivity of the hydrogenation reaction? 2) Does
this effect also take place during the hydrogenation of ethyl
pyruvate, the most common and most investigated sub-
strate? Additionally, we were interested in the more general
applicability of the hydrosilylation reaction as a means for
simple synthetic modification of cinchona alkaloids which,
besides the applications in hydrogenation catalysis, form
Scheme 2. Synthesis of the chiral modifiers 4a–d and their precur-
sors 3a–d. i) TMSCl, Et3N, THF; ii) R1R2R3SiH, Karstedt’s cata-
active catalysts or stoichiometric reagents for a wide array lyst, toluene, 80–90 °C; iii) MeOH, reflux.
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Synthesis of Chiral Catalyst Modifiers by Hydrosilylation of Cinchonidine
FULL PAPER
The corresponding 11-silyl-substituted 10,11-dihydrocin- of configuration at the silicon atom upon the hydro-
chonidines 4a–d were then obtained in 70–92% isolated silylation reaction.[19]
yields after refluxing compounds 3a–d in methanol in order
Despite several attempts, single crystals suitable for X-
to remove the 9-O-TMS protecting group followed by stan- ray structure determination could only be obtained from
dard purification/washing and/or crystallization procedures. the 11-triphenylsilyl-substituted compound 4b after
All compounds 3a–d and 4a–d were fully characterized by recrystallization from methanol. The molecular structure of
HRMS analysis and by 1H and 13C NMR spectroscopy. No 4b is displayed in Figure 2 with selected torsion angles col-
racemization of the chiral silyl group was observed in the lected in Table 1. All compounds 4a–d were then, together
hydrosilylation of 2 with (+)-(R)-methyl(1-naphthyl)phen- with (–)-cinchonidine (1), evaluated as chiral modifiers in
1
ylsilane, as indicated by the single H NMR methyl reso- the hydrogenation of ethyl pyruvate and 1-phenylpropane-
nance from the silicon-bound methyl group of compounds 1,2-dione on a heterogeneous Pt/Al2O3 catalyst.
3c and 4c. The proposed stereochemical configuration of
Table 1. Selected torsion angles [°] for cinchonidine (1)[20] and 11-
the chiral silicon atom in compounds 3c and 4c, as illus-
triphenylsilyl-10,11-dihydrocinchonidine (4b) for comparison of the
trated for 4c in Figure 1, is based on the expected retention
orientations of their quinoline and quinuclidine moieties.
1
4b
N(1)–C(8)–C(9)–C(4Ј)
C(7)–C(8)–C(9)–C(4Ј)
N(1)–C(8)–C(9)–O(1)
C(7)–C(8)–C(9)–O(1)
C(4ЈA)–C(4Ј)–C(9)–O(1)
C(3Ј)–C(4Ј)–C(9)–O(1)
C(3Ј)–C(4Ј)–C(9)–C(8)
C(4ЈA)–C(4Ј)–C(9)–C(8)
158.0(6)
–76.1(4)
–77.9(4)
48.0(7)
159.1(7)
–22.6(9)
101.5(7)
–76.8(7)
150.8(2)
–81.8(3)
–86.0(2)
41.3(3)
150.3(2)
–27.8(3)
95.5(3)
–86.4(3)
Hydrogenation of Ethyl Pyruvate
The enantioselective hydrogenation of α-oxo esters on
cinchona alkaloid modified Pt catalysts was originally de-
scribed by Orito, Imai and Niwa.[21] In 1978 it was reported
that cinchonidine-modified Pt/C was active for the enantio-
selective hydrogenation of methyl pyruvate to (+)-(R)-
methyl lactate in ethanolic solution at 70 bar pressure and
ambient temperature.[21e] Over the past decade extensive ef-
forts have been carried out to optimize the reaction condi-
tions and understand the mechanism of enantiodifferenti-
ation in the hydrogenation of both methyl and ethyl pyr-
uvate. Hydrogenation of ethyl pyruvate to the correspond-
ing ethyl lactate, as illustrated in Scheme 3, has become the
prominent model reaction in this field. Most of the experi-
mental parameters such as the employed catalyst (metal,
support, particle size, etc.), the structure and concentration
of the modifier, solvent effects, mass-transfer limitations
and hydrogen pressure have been systematically studied for
this system.[2] In spite of the extensive literature on the sub-
ject, only a few studies have addressed the influence of dis-
tal modifier substitution at the C-3 quinuclidine atom on
enantioselectivity.[6b] Thus, we felt motivated to investigate
the new modifiers described in the present work also in the
hydrogenation of ethyl pyruvate.
Figure 1. Structures of the chiral modifiers 4a–d.
Figure 2. Molecular structure of 11-triphenylsilyl-10,11-dihydrocin-
chonidine (4b).
Scheme 3. Hydrogenation of ethyl pyruvate.
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I. Busygin, E. Toukoniitty, R. Sillanpää, D. Yu. Murzin, R. Leino
FULL PAPER
Under the experimental conditions employed here (P = conversion. The first observed ee is slightly lower for 1 and
10 bar H2, cEtPy = 0.1 m, T = 15 °C), hydrogenation of ethyl 4a, however, this can be attributed to the well-documented
pyruvate on 5 wt-% Pt/Al2O3 modified by the parent com- initial transient behaviour of the ee at low ethyl pyruvate
pound cinchonidine (1) afforded (R)-ethyl lactate in 84% conversion levels.[22]
ee, a considerably high enantioselectivity in toluene without
All modifiers decreased the reaction rate (Table 3). The
acid additives. Enantiomeric excesses obtained with the 11- racemic reaction was up to three fold faster than the lowest
silyl-substituted modifiers 4a–4d were in all cases slightly modified reaction rate using 4c while being slightly slower
lower (ee = 62–73%) compared to 1 (Table 2). The influence than the reaction modified by cinchonidine. Kinetic curves
of the distal substituent on the ee is minor as triethyl (4a), are collected in Figure 4. Among the studied reactions, ra-
triphenyl (4b) and methyl(1-naphthyl)phenyl substitution cemic hydrogenation of ethyl pyruvate in the absence of chi-
(4c) result in practically the same ee values. Likewise, the ral modifier is the fastest (Figure 4) and the initial reaction
additional stereocenter in the chiral-at-silicon modifier 4c rate with cinchonidine (1) is about the same order of magni-
appears to have a negligible, if any, influence on the enanti- tude (Table 3). The chirally modified systems are ranked in
odifferentiation. The 11,11Ј-bridged bis(cinchonidine) 4d the following order of decreasing reaction rate: 1 Ͼ 4a Ͼ
gave a lower enantioselectivity (ee = 62%) than the other 4b Ͼ 4d Ͼ 4c. The initial reaction rate does not correlate
three modifiers 4a–c, yet the difference is relatively small. with the observed ee values (Table 2).
Also, it should be noted that in compensation for its two
anchoring moieties, the applied concentration of modifier
4d was only one half of that employed for modifiers 4a–c,
Table 3. Initial rates of the ethyl pyruvate (EtPy) and 1-phenylpro-
pane-1,2-dione (A) hydrogenation in the presence of the chiral
modifiers 4a–d and cinchonidine.
while it remains unclear at present whether 4d adsorbs via
both of its quinoline moieties or not. The dependence of
the ee on the ethyl pyruvate conversion is illustrated in Fig-
ure 3. A constant ee with increasing ethyl pyruvate conver-
sion was observed for 1, 4b, 4c and 4d, whereas 4a gave the
maximum selectivity of ee = 77% at approximately 20%
conversion after which it decreased slighltly to 66% at 60%
[a]
1
–
4a
4b
4c
4d
Initial rate[b] 111.6 96.2
73.0
0.91
14.0
0.98
53.0
0.99
4.2
30.4
0.90
3.75
0.99
38.6
0.98
5.7
EtPy
A
R2[c]
Initial rate[b] 18.6
R2[c]
0.99
0.99
0.98
21.2
0.99
0.96
0.99
[a] Racemic hydrogenation in the absence of modifier. [b] The initial
rates were calculated by using the linear approximation of the kin-
etic data obtained over the time interval from 3 to 10 min for EtPy
and from 3 to 20 min for A after reaction start and are expressed
in 10–4 ×mol min–1 g–1cat. [c] R2: coefficient of determination for
linear approximation.
Table 2. Hydrogenation of ethyl pyruvate.
Modifier
ee(R) [%][a]
Conversion [mol%][b]
1
84
0
68
68
73
62
100
100
57
81
70
[c]
–
4a
4b
4c
4d
46
[a] At 50% conversion of EtPy. [b] Conversion after 1 h. [c] Race-
mic hydrogenation in the absence of modifier.
Figure 4. Hydrogenation kinetics of ethyl pyruvate in toluene at
15 °C. Catalyst: 5 wt-% Pt/Al2O3 modified in situ. [a] 0.5 mol-equiv.
of 4d used in comparison to 4a–c.
Hydrogenation of 1-Phenylpropane-1,2-dione
1-Phenylpropane-1,2-dione (A) is a prochiral unsymmet-
rical diketone which upon hydrogenation produces four dif-
ferent chiral hydroxy ketones (B, C, D and E) and four diols
(F, G, H and I) (Scheme 1). The first stage of the hydrogena-
Figure 3. Enantiomeric excess (ee) in the hydrogenation of ethyl
pyruvate in the presence of chiral modifiers 4a–d and cinchonidine
[a]
in toluene at 15 °C and 10 bar of H2. 0.5 mol-equiv. of 4d used
in comparison to 4a–c.
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Synthesis of Chiral Catalyst Modifiers by Hydrosilylation of Cinchonidine
FULL PAPER
tion reaction produces two regioisomers, 1-hydroxy-1-phen-
ylpropanone and 2-hydroxy-1-phenylpropanone, the former
being the major product. Both regioisomers are formed as
pairs of enantiomers (B/C and D/E in Scheme 1). In the
second stage, the hydroxy ketones react further to the corre-
sponding diols, which again are formed as two pairs of
enantiomers (F/G and H/I). At the hydroxy ketone stage,
an increase of the intermediate ee takes place due to kinetic
resolution in the presence of cinchonidine, i.e., both C and
D react further to diols faster than B and E resulting in an
increase of enantiomeric excess. The predominant product
obtained in the hydrogenation of 1-phenylpropane-1,2-di-
one over cinchonidine-modified Pt catalysts is the (–)-(R)-
1-hydroxy-1-phenylpropan-2-one stereoisomer B.
The hydrogenation kinetics of the 1-phenylpropane-1,2-
dione in the presence of the different chiral modifiers are
presented in Figure 5 with enantiomeric excesses vs. conver-
sion in Figure 6. Catalyst modification by the 11-triethyl-
silyl-substituted cinchonidine derivative 4a in toluene pro-
vided a similar ee enhancement compared to cinchonidine
(ee = 70% vs. 55%) as observed earlier with the 11-trieth-
oxysilyl analogue in ethyl acetate (Table 4).[17] Also the re-
gioselectivity (B+C vs. D+E) was slightly enhanced. The 11-
triphenylsilyl analogue 4b gave a similar ee than obtained
with 1 (ee = 53% and 55%, respectively). With the chiral-
at-silicon compound 4c, the ee dropped to 41%, indicating
again that distal modifier substitution has a notable influ-
ence in the hydrogenation of A. This is in contrast to the
observations reported here for the hydrogenation of ethyl
pyruvate (vide supra) where all three modifiers 4a–c pro-
vided similar enantiomeric excesses of approximately 70%.
Analogously to the ethyl pyruvate case, the lowest enantio-
meric excess in the hydrogenation of A was obtained with
the bis(cinchonidine) modifier 4d (ee = 24%) which again,
in compensation for its two anchoring quinoline moieties,
was applied in a concentration of one half of that employed
for modifiers 4a–c.
Figure 5. Hydrogenation kinetics of 1-phenylpropane-1,2-dione in
toluene at 15 °C. Catalyst: 5 wt-% Pt/Al2O3 modified in situ.
0.5 mol-equiv. of 4d used in comparison to 4a–c.
[a]
Figure 6. Enantiomeric excess (ee) in the hydrogenation of 1-phen-
ylpropan-1,2-dione in the presence of chiral modifiers in toluene at
15 °C and 10 bar of H2. [a] 0.5 mol-equiv. of 4d used in comparison
to 4a–c.
The distribution of diols was very similar with all modifi-
ers evaluated with the main diol being the (1R,2S) dia-
stereomer F with 51% Ͻ S Ͻ 60% and ee = 23–36%. The viously for cinchonidine-modified catalyst in ethyl ace-
regioselectivity (rs) varied slightly with the chiral modifier tate,[14d] i.e., high ee and high rs are interrelated.
selected from 4.1 during racemic reaction to 2.1–5.3 in the
Conversions of A achieved after 2 h of reaction under
enantioselective hydrogenations. Interestingly, the modifier the standard conditions in toluene ranged from 48 to 98%
4d clearly increases the reaction towards D and E resulting indicating strong dependence of the reaction rate on the
in lower rs than observed during a racemic hydrogenation. modifier structure. The conversion vs. time behaviour is
The rs correlates well with the obtained ee as reported pre- similar for 1, 4a and the racemic hydrogenation, as well as
Table 4. Hydrogenation of 1-phenylpropan-1,2-dione (A) in the presence of chiral modifiers.
rs[c]
Conversion
[mol%][d]
Diols
[b]
[b]
[b]
Modifier ee(R)–1
ee(RS)
S(RR+SS)
[%]
S(RS)
[%]
S(SR)
[%]
[%][a]
[%][a]
[mol%][d]
1
55
0
70
53
41
24
33
–1
36
23
23
34
19
17
11
17
19
15
54
41
60
51
50
57
27
42
28
32
31
28
4.5
4.1
5.3
4.2
3.8
2.1
98
29
47[f]
21
4
7
6
[e]
–
97[f]
98
4a
4b
4c
4d
52
64
48
[a] At 50% conversion of A; for the definition, see Exp. Sect. [b] S = selectivity; for the definition, see Exp. Sect. [c] rs = regioselectivity;
for the definition, see Exp. Sect. [d] After 2 h. [e] Racemic hydrogenation in the absence of modifier. [f] After 1.5 h.
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FULL PAPER
in the series 4b, 4c and 4d, the former ones being fourfold ity–activity relationships, which in turn help to rationalize
faster than the latter three. Reaction rates obtained with 1 feasible reaction mechanisms. The modifiers investigated
and the 11-triethylsilyl-substituted modifier 4a are signifi- here decreased the reaction rate with respect to the racemic
cantly higher than those obtained with all other modifiers. hydrogenation (Table 3) and the activity could not be corre-
Compound 4a induces a significant enhancement in both lated with the enantioselectivity. The experimentally ob-
enantio- and regioselectivity, whereas the initial reaction tained initial rates with ethyl pyruvate, at first sight, are in
rate is lower than that obtained with 1.
conflict with the known phenomenon of rate acceleration
induced by the presence of chiral modifiers.[24] However,
noteworthy is that in the present work a relatively low ethyl
pyruvate concentration was used (0.1 m). Previously, a rate
Discussion
All new modifiers prepared were characterized by 1H and deceleration has been observed at low substrate concentra-
13C NMR spectroscopy, high-resolution MS and elemental tion in ethyl pyruvate hydrogenation,[25] indicating that the
analysis. Satisfactory elemental analyses within the range of rate acceleration and enantioselectivity are not always inter-
0.4% were obtained in all cases except for some of the 9- related. In the hydrogenation of A it is well accepted that
O-TMS-protected precursors (none of which were exhaus- the modified reaction has the same or lower rate than the
tively purified and are not claimed here as “pure” com- racemic reaction[14d] while ee values up to 70% can be ob-
pounds) and the bis(cinchonidine) compound 4d, all of tained. It is noteworthy to mention that experiments with
which gave satisfactory H and N analytical data deviating A have always been carried out at very low substrate con-
only by a maximum of 0.8% in their carbon analyses. No- centrations (Ͻ 0.1 m), thus, it would be interesting to test
tably, all of the compounds 3b–3d and 4d yielding slight whether the reaction also exhibits a rate acceleration at
deviations in C analyses contain either two or four silicon much higher substrate concentrations as observed in the
atoms while giving entirely satisfactory H and N microana- ethyl pyruvate case.
lytical data. Considering that significant impurities were
The results here with ethyl pyruvate are in line with pre-
not detected in the NMR analysis of these compounds, the vious observations[2,6] that the distal modifier part has a
discrepancies are possibly a result from the disturbing ef- relatively small influence on the ee even when bulky substit-
fects of silicon in the carbon measurements. As observed uents are involved. Even the bridged bis(cinchonidine)
earlier for the 11-triethoxysilyl-substituted analogue, the modifier 4d results in a relatively high ee and the disilane
distal substitution in position 11 does not change the sign linking does not greatly alter the modifier performance, al-
of the optical rotation of these cinchonidine derivatives; all though it reduces the reaction rate significantly.
compounds 4a–c gave negative optical rotations in analogy
to cinchonidine. Due to the poor solubility of 4d in chloro- A, where the distal substituents can either notably decrease
form and alcohols, its optical rotation was not measured. or increase the ee with respect to cinchonidine. The en-
The same reasoning clearly does not apply in the case of
The crystallographic data of 11-(triphenylsilyl)-10,11-di- hancement of the ee obtained here in the hydrogenation of
hydrocinchonidine (4b) (molecular structure displayed in A with 4a in toluene and observed earlier with its triethoxy-
Figure 2) demonstrates that this modifier, in the crystalline silyl analogue in ethyl acetate is difficult to explain at pres-
state, exists in the open(3) cinchonidine conformation. ent, considering that similar enhancement was not observed
Based on the previous ab initio calculations with cinchoni- in the hydrogenation of ethyl pyruvate. However, as shown
dine and 11-(triethoxysilyl)-10,11-dihydrocinchonidine,[17] previously by us,[14c,26] the enantiodifferentiating mecha-
the most stable conformations for both of these compounds nisms for the two substrates are clearly different and we
were very similar open(3) forms. Thus, even relatively large propose this effect to have mainly a steric origin. It is tempt-
substituents in the distal C-3 position would not appear to ing to speculate that at the substrate–modifier complexation
result in dramatic changes in the conformational equilib- stage, the distal 11-triethylsilyl or 11-triethoxysilyl substitu-
rium. In ethyl pyruvate hydrogenation the cinchonidine ent increases the population of the open(3)-like confomer
open(3) conformation is assumed to be the actor species leading to higher ee values, whereas bulkier substituents
based on several theoretical and experimental arguments.[23] such as those in 4b and 4c may have a conflicting interac-
Taking into account the central role of the open(3) confor- tion with the diketone substrate resulting in lower enantio-
mation of cinchonidine (1) in toluene [population of the selectivities. Nevertheless, the results obtained here are
open(3) conformation Popen = 70%] and the similar ee val- promising, demonstrating unambiguously that the ee ob-
ues obtained with 1 and the modifiers 4a–d in the hydrogen- tained with cinchonidine as the chiral modifier in the
ation of ethyl pyruvate, one would expect that the open(3) hydrogenation of A is by no means the maximum value ob-
conformation is the predominant conformation in toluene tainable and that by proper substituents in the distal
for all modifiers evaluated here. The chiral-at-silicon com- position of the modifier, higher ee values can be achieved.
pound 4c could in principle adsorb on Pt also by anchoring In a separate study,[26] we have evaluated a series of 16
via its Si–naphthyl substituent, however, given the similar chiral catalyst modifiers derived from cinchonidine, cincho-
ee values in the ethyl pyruvate case this possibility can be nine and quinine structures in the hydrogenation of A, none
considered very unlikely.
of which provided higher ee values in the first hydrogena-
Dependence of the reaction rate and ee on the modifier tion step as compared to the parent modifier (–)-cinchoni-
structure gives mechanistically important structure–selectiv- dine.
2816
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2811–2821

Synthesis of Chiral Catalyst Modifiers by Hydrosilylation of Cinchonidine
FULL PAPER
(TMS). The chemical shifts are expressed in ppm downfield from
TMS. Signal multiplicities are given in parentheses [br = broad
unresolved multiplet (1H NMR) or signal broadening (13C NMR);
Conclusions
The effect of distal modifier substitution in the enantio-
selective hydrogenation of ethyl pyruvate and 1-phenylpro- ur = unresolved multiplet without broadening (1H NMR)]. 1H
NMR spectra were finally analyzed with the PERCH software.[29]
pane-1,2-dione on chirally modified Pt catalyst was investi-
The numbering system for cinchonidine derivatives is presented in
gated. Bulky aromatic substituents on the 11-silyl group at-
Figure 7. Polarimetric measurements were carried out with a Per-
tached to the quinuclidine C-3 position of cinchonidine via
kin–Elmer 241 polarimeter with a cell volume of 1 mL and a cell
the two-carbon linker decreased the rate of hydrogenation.
length of 10 cm. Optical rotations are given in units of
In the ethyl pyruvate hydrogenation, the distal modification
10–1 °cm2 mol–1. Microanalysis was conducted at the Helsinki Uni-
does not play a crucial role with all 11-substituted modifiers
yielding slightly lower ee values (62–73%) in toluene com-
versity of Technology, Finland, and A. N. Nesmeyanov Institute of
Organoelement Compounds, Russian Academy of Sciences, Mos-
pared to cinchonidine (ee = 84%). The reaction rate was
lower in all chirally modified reactions as compared to the
racemic reaction in the absence of a modifier. The hydro-
genation of 1-phenylpropane-1,2-dione is more sensitive to
distal substitution effects and compared to cinchonidine (ee
= 55%), the ee can be notably higher (ee = 70%) or lower
(ee = 24%), depending on the substitution pattern of the
modifier employed. Enhancement of the ee was obtained
here with the sterically least demanding 11-triethylsilyl sub-
stituent, in a similar fashion to the previously obtained re-
sult with the 11-triethoxysilyl substituent. The differences
observed in the structure–selectivity–activity correlations
with ethyl pyruvate and 1-phenylpropane-1,2-dione sub-
strates clearly indicate that the mechanisms of enantiodif-
ferentiation on cinchona alkaloid modified Pt hydrogena-
tion catalyst systems are different for the two. Furthermore,
it was demonstrated that (–)-cinchonidine is not the optimal
modifier structure in the hydrogenation of A and notably
enhanced enantioselectivities can be obtained by simple
chemical modifications of the parent structure, a result
cow, Russia.
Figure 7. Numbering system for 4c.
11-(Triethylsilyl)-10,11-dihydrocinchonidine (4a): To a solution of 2
(2.0 g, ca. 4.9 mmol of pure substance) in toluene (5 mL) were
added two drops of Karstedt’s catalyst. After stirring at room tem-
perature for 10 min, triethylsilane (0.64 g, 5.5 mmol.) was added.
The reaction mixture was stirred at 80–90 °C for 4 h. After cooling
to room temperature, the solvent was evaporated and the residue
promising with respect to the broader applicability of chi- purified by gradient flash chromatography (CH2Cl2/MeOH, 20:1
Ǟ 10:1) to yield 1.78 g of 11-(triethylsilyl)-9-O-(trimethylsilyl)-
10,11-dihydrocinchonidine (3a) (3.7 mmol, 75%) as a yellowish oil.
rally modified heterogeneous catalysts for enantioselective
synthesis.
3
1H NMR (CDCl3): δ = 8.88 (d, J2Ј,3Ј = 4.5 Hz, 1 H, H-2Ј), 8.15
4
3
(dd, J8Ј,6Ј = 1.2, J8Ј,7Ј = 8.5 Hz, 1 H, H-8Ј), 8.13 (br., 1 H, H-5Ј),
4
3
3
7.71 (ddd, J7Ј,5Ј = 1.3, J7Ј,6Ј = 6.8, J7Ј,8Ј = 8.5 Hz, 1 H, H-7Ј),
7.57 (ddd, J6Ј,8Ј = 1.2, J6Ј,7Ј = 6.8, J6Ј,5Ј = 8.5 Hz, 1 H, H-6Ј),
7.50 (br., 1 H, H-3Ј), 5.59 (br., 1 H, H-9), 3.39 (br., 1 H, H-6b),
Experimental Section
4
3
3
General Remarks: All reactions with air-sensitive reagents were car-
ried out under argon using standard Schlenk, vacuum or glove-box
techniques. THF was dried and distilled under argon from sodium/
benzophenone prior to use. Toluene was dried over molecular si-
3
2
3,08 (dd, J2a,3 = 10.0, J2a,2b = 13.4 Hz, 1 H, H-2a), 2.99 (br., 1
H, H-8), 2.65 (br., 1 H, H-6a), 2.31 (dm, 1 H, H-2b), 1.82–1.69 (m,
3 H, H-4, H-5b, H-7b), 1.46–1.36 (m, 3 H, H-3, H-5a, H-7a), 1.20–
3
eves (4 Å). (–)-Cinchonidine (Aldrich, 96%), triethylsilane (Gelest, 1.10 (m, 2 H, H-10), 0,84 (t, J14,13 = 7.9 Hz, 9 H, SiCH2CH3),
3
99+%), triphenylsilane (Fluka, Ն99%) and platinum–divinyltet-
ramethyldisiloxane complex (Karstedt’s catalyst, 2.1–2.4% Pt con-
centration in xylene, Gelest) were used as received. Synthesis of 9-
O-(trimethylsilyl)cinchonidine was carried out as described pre-
viously,[17] 1,2-bis(dimethylsilyl)ethane was prepared by reduction
of 1,2-bis(chlorodimethylsilyl)ethane (Gelest, 97%) with LiAlH4
and vacuum-distilled prior to use.[27] The chiral silane (+)-(R)-
methyl(1-naphthyl)phenylsilane, was prepared according to a litera-
ture procedure.[28] For use in the catalytic hydrogenation reactions,
1-phenylpropane-1,2-dione (Aldrich, 99%) and ethyl pyruvate
(Fluka, Ն97%) were vacuum-distilled before use, whereas toluene
(J. T. Baker, Ͼ99.5%) and cinchonidine (Fluka, 98%) were used as
received. Melting points were determined in open glass capillaries
and are uncorrected. Electron impact high-resolution mass spectra
(HRMS) were obtained with a Fisons ZabSpec mass spectrometer
at 70 eV. NMR spectra were recorded at 303 K in CDCl3 and [D4]
methanol (ca. 0.15 m solutions) using JEOL JNM-L 400 or JNM-A
500 NMR spectrometers and referenced against tetramethylsilane
0.41 (q, J13,14 = 7.9 Hz, 6 H, SiCH2CH3), 0,38 (m, 2 H, H-11),
0.04 (s, 9 H, SiCH3) ppm. 13C NMR (CDCl3): δ = 150.00 (C-2Ј),
149.58 (C-4Ј), 148.47 (C-8aЈ), 130.45 (C-8Ј), 128.95 (C-7Ј), 126.57
(C-6Ј), 125.56 (C-4aЈ), 123.22 (C-5Ј), 118.75 (C-3Ј), 73.13 (C-9),
61.45 (C-8), 59.08 (C-2), 43.22 (C-6), 39.29 (C-3), 28.59 (2 C, C-5,
C-10), 25.62 (C-4), 20.91 (C-7), 9.08 (C-11), 7.43 (3 C, SiCH2CH3),
3.25 (3 C, SiCH2CH3), 0.24 (3 C, SiCH3) ppm. HRMS: calcd. for
C28H46N2OSi2 482.3149; found 482.3145. Next, a solution of 3a
(0.60 g, 1.24 mmol) in methanol (25 mL) with addition of some
crystals of potassium carbonate was refluxed for 20 h. Evaporation
of the solvent and the subsequent washing with pentane left 0.47 g
(1.14 mmol, 92%) of 4a as an analytically pure white solid. 1H
3
NMR(CDCl3): δ = 8.74 (d, J2Ј,3Ј = 4.5 Hz, 1 H, H-2Ј), 8.05 (dd,
3
4
4J8Ј,6Ј = 1.2, J8Ј,7Ј = 8.5 Hz, 1 H, H-8Ј), 7.93 (dd, J5Ј,7Ј = 1.3,
3J5Ј,6Ј = 8.5 Hz, 1 H, H-5Ј), 7.60 (ddd, J7Ј,5Ј = 1.3, J7Ј,6Ј = 6.8,
4
3
3J7Ј,8Ј = 8.5 Hz, 1 H, H-7Ј), 7.56 (d, J3Ј,2Ј = 4.5 Hz, 1 H, H-3Ј),
3
4
3
3
7.28 (ddd, J6Ј,8Ј = 1.2, J6Ј,7Ј = 6.8, J6Ј,5Ј = 8.5 Hz, 1 H, H-6Ј),
5.61 (d, J9,8 = 3.8 Hz, 1 H, H-9), 5.17 (s, 1 H, OH), 3.46 (m, 1 H,
3
Eur. J. Org. Chem. 2005, 2811–2821
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2817

I. Busygin, E. Toukoniitty, R. Sillanpää, D. Yu. Murzin, R. Leino
FULL PAPER
H-6b), 3,04 (m, 1 H, H-8), 2.99 (dd, 3J2a,3 = 10.0, 2J2a,2b = 13.5 Hz, 28.56 (C-10), 28.17 (C-5), 25.22 (C-4), 20.92 (C-7), 11.04 (C-11)
1 H, H-2a), 2.54 (m, 1 H, H-6a), 2.30 (dm, 1 H, H-2b), 1.79 (m, 1
ppm. [α]2D4 = –59.3 (c = 0.054 m in CHCl3). M.p. 198–201 °C.
H, H-4), 1.77–1.70 (m, 2 H, H-5b, H-7b), 1.42–1.33 (m, 3 H, H-3,
H-5a, H-7a), 1.19–1.09 (m, 2 H, H-10), 0,83 (t, J14,13 = 7.9 Hz, 9 C40H46N2OSi2 (554.78): calcd. C 80.10, H 6.90, N 5.05; found C
HRMS: calcd. for C37H38N2OSi 554.2753; found 554.2755.
3
H, SiCH2CH3), 0.41 (q, 3J13,14 = 7.9 Hz, 6 H, SiCH2CH3), 0,37 (m,
2 H, H-11) ppm. 13C NMR (CDCl3): δ = 150.09 (C-2Ј), 149.89 (C-
4Ј), 148.17 (C-8aЈ), 130.15 (C-8Ј), 128.93 (C-7Ј), 126.53 (C-6Ј),
125.76 (C-4aЈ), 123.11 (C-5Ј), 118.35 (C-3Ј), 71.87 (C-9), 60.31 (C-
8), 58.73 (C-2), 43.38 (C-6), 39.23 (C-3), 28.63 (C-10), 28.41 (C-5),
25.55 (C-4), 21.30 (C-7), 9.10 (C-11), 7.47 (3 C, SiCH2CH3), 3.27
(3 C, SiCH2CH3) ppm. [α]2D4 = –66.5 (c = 0.056 m in CHCl3). M.p.
220–222 °C. HRMS: calcd. for C25H38N2OSi 410.2753; found
410.2752. C25H38N2OSi (410.67): calcd. C 73.12, H 9.33, N 6.82;
found C 72.99, H 9.33, N 6.80.
80.18, H 6.97, N 4.91.
11-[(R)-methyl(1-naphthyl)phenylsilyl]-10,11-dihydrocinchonidine
(4c): To a solution of 2 (1.0 g, ca. 2.45 mmol of pure substance) in
toluene (5 mL) were added two drops of Karstedt’s catalyst. After
stirring at room temperature for 10 min, (+)-(R)-methyl(1-naph-
thyl)phenylsilane (0.61 g, 2.45 mmol) was added. The reaction mix-
ture was stirred at 80–90 °C for 4 h and then at room temperature
for 8 h. After evaporation of the solvents, the residue was purified
by two consecutive flash chromatography procedures (CH2Cl2/
MeOH, 20:1) to yield 0.58 g (0.94 mmol, 38%) of 11-[(R)-methyl(1-
naphthyl)phenylsilyl]-9-O-(trimethylsilyl)-10,11-dihydrocinchoni-
dine (3c) as white amorphous material. 1H NMR (CDCl3): δ = 8.87
11-(Triphenylsilyl)-10,11-dihydrocinchonidine (4b): To a solution of
2 (2.0 g, ca. 4.9 mmol of pure substance) in toluene (5 mL) were
added two drops of Karstedt’s catalyst. After stirring at room tem-
perature for 10 min, triphenylsilane (1.28 g, 4.9 mmol) was added.
The reaction mixture was stirred at 80–90 °C for 2 h. After cooling
to room temperature, the solvent was evaporated and the residue
purified by flash chromatography (CH2Cl2/MeOH, 20:1) to yield
2.54 g of 11-(triphenylsilyl)-9-O-(trimethylsilyl)-10,11-dihydrocin-
3
4
3
(d, J2Ј,3Ј = 4.5 Hz, 1 H, H-2Ј), 8.15 (dd, J8Ј,6Ј = 1.2, J8Ј,7Ј
=
=
=
4
8.5 Hz, 1 H, H-8Ј), 8.08–8.03 (br., 1 H, H-5Ј), 7.81 (dd, J20,18
3
4
3
1.2, J20,19 = 8.2 Hz, 1 H, H-20), 7.80 (dd, J16,14 = 1.0, J16,15
4
3
8.5 Hz, 1 H, H-16), 7.78 (dd, J17,19 = 1.3, J17,16 = 8.1 Hz, 1 H,
4
3
3
H-17), 7.71 (ddd, J7Ј,5Ј = 1.3, J7Ј,6Ј = 6.8, J7Ј,8Ј = 8.5 Hz, 1 H,
4
3
H-7Ј), 7.61 (dd, J14,16 = 1.0, J14,15 = 6.8 Hz, 1 H, H-14), 7.54
4
3
3
(ddd, J6Ј,8Ј = 1.2, J6Ј,7Ј = 6.8, J6Ј,5Ј = 8.6 Hz, 1 H, H-6Ј), 7.45–
1
chonidine (3b) (4.1 mmol, 83%) as white amorphous material. H
4
3
7.42 (br., 1 H, H-3Ј), 7.41 (dd, Jo–,p– = 1.4, Jo–,m– = 7.6 Hz, 2 H,
o-H), 7.35 (m, 2 H, H-18, H-19), 7.28–7.22 (m, 2 H, H-15, p-H),
7.20 (m, 2 H, m-H), 5.57 (br., 1 H, H-9), 3.36 (br., 1 H, H-6b), 3.00
(m, 1 H, H-2a), 2.82 (br., 1 H, H-8), 2.60 (m, 1 H, H-6a), 2.24 (dm,
1 H, H-2b), 1.76 (m, 1 H, H-4), 1.70–1.63 (m, 2 H, H-5b, H-7b),
1.46–1.39 (m, H, H-3), 1.39–1.31 (m, 1 H, H-5a) 1.29–1.06 (m, 5
H, H-7a, H-10, H-11), 0.59 (s, 3 H, SiCH3) 0.01 [s, 9 H, Si(CH3)3]
ppm. 13C NMR (CDCl3): δ = 150.00 (C-2Ј), 149.47 (C-4Ј), 148.48
(C-8aЈ), 137.98 (C-16a), 137.04 (C-13), 134.86 (C-14), 134.64 (i-C),
134.31 (o-C), 133.42 (C-20a), 130.49 (C-8Ј), 130.28 (C-16), 129.10
(C-17), 128.98 (2 C, p-C, C-7Ј), 128.43 (C-20), 127.88 (m-C), 126.62
(C-6Ј), 125.59 (C-18), 125.48 (C-4aЈ), 125.38 (C-15), 125.01 (C-19),
123.15 (C-5Ј), 118.81 (C-3Ј), 74.03 (C-9), 61.31 (C-8), 58.98 (C-2),
43.19 (C-6), 38.81 (C-3), 28.69 (C-10), 28.43 (C-5), 25.38 (C-4),
20.89 (C-7), 12.91 (C-11), 0.24 [3 C, Si(CH3)3], –2.83 (SiCH3) ppm.
HRMS: calcd. for C39H46N2OSi2 614.3149; found 614.3147.
C39H46N2OSi2 (614.97): calcd. C 76.17, H 7.54, N 4.56; found C
75.34, H 7.37, N 4.60. Next, a solution of 3c (0.22 g, 0.36 mmol)
in methanol (10 mL) with addition of some crystals of potassium
carbonate was refluxed for 4 h. After cooling to room temperature,
a white solid precipitated. Recrystallization from methanol gave
0.18 g (0.33 mmol, 92%) of 4c as an analytically pure white solid.
3
NMR (CDCl3): δ = 8.87 (d, J2Ј,3Ј = 4.5 Hz, 1 H, H-2Ј), 8.16 (dd,
3
4J8Ј,6Ј = 1.2, J8Ј,7Ј = 8.5 Hz, 1 H, H-8Ј), 8.06 (br., 1 H, H-5Ј), 7.71
4
3
3
(ddd, J7Ј,5Ј = 1.2, J7Ј,6Ј = 6.8, J7Ј,8Ј = 8.5 Hz, 1 H, H-7Ј), 7.54
4
3
3
(ddd, J6Ј,8Ј = 1.2, J6Ј,7Ј = 6.8, J6Ј,5Ј = 8.5 Hz, 1 H, H-6Ј), 7.44
(br., 1 H, H-3Ј), 7.40 (m, 6 H, o-H), 7.31 (m, 3 H, p-H), 7.22 (m,
6 H, m-H), 5.59 (br., 1 H, H-9), 3.38 (br., 1 H, H-6b), 3,02 (dd,
3J2a,3 = 9.7, 2J2a,2b = 13.4 Hz, 1 H, H-2a), 2.83 (br., 1 H, H-8), 2.61
(m, 1 H, H-6a), 2.26 (dm, 1 H, H-2b), 1.82 (m, H-4), 1.74–1.65 (m,
2 H, H-5b, H-7b), 1.50–1.43 (m, H, H-3), 1.41–1.29 (m, 2 H, H-
10), 1.31–1.25 (m, 2 H, H-5a, H-7a), 1.25–1.19 (m, 2 H, H-11),
0.01 (s, 9 H, SiCH3) ppm. 13C NMR (CDCl3): δ = 149.90 (C-2Ј),
149.44 (C-4Ј), 148.41 (C-8aЈ), 135.48 (6 C, o-C), 134.96 (3 C, i-C),
130.42 (C-8Ј), 129.37 (3C, p-C), 128.90 (C-7Ј), 127.77 (6C, m-C),
126.56 (C-6Ј), 125.46 (C-4aЈ), 123.14 (C-5Ј), 118.64 (C-3Ј), 73.44
(C-9), 61.19 (C-8), 58.90 (C-2), 43.18 (C-6), 38.87 (C-3), 28.58 (C-
10), 28.37 (C-5), 25.27 (C-4), 20.57 (C-7), 11.06 (C-11), 0.17 (3 C,
SiCH3) ppm. [α]2D4 = –74.7 (c = 0.08 m in CHCl3). HRMS: calcd.
for C40H46N2OSi2 626.3149; found 626.3152. C40H46N2OSi2
(626.98): calcd. C 76.63, H 7.40, N 4.47; found C 75.92, H 7.23, N
4.42. Next, a solution of 3b (1.71 g, 2.7 mmol) in methanol (40 mL)
with addition of some crystals of potassium carbonate was refluxed
for 20 h. Evaporation of the solvent and recrystallization of the
residue from methanol gave 1.15 g of 4b (2.0 mmol, 76%) as an
analytically pure white solid. Crystals suitable for X-ray structure
determination were obtained by recrystallization from methanol.
1H NMR (CDCl3/CD3OD, 1:2): δ = 8.81 (d, J = 4.5 Hz, 1 H, H-
3
4
3
4
2Ј), 8.11 (dd, J = 1.3, J = 8.5 Hz, 1 H, H-8Ј), 8.05 (dd, J = 1.5,
3J = 8.6 Hz, 1 H, H-5Ј), 7.81–7.69 (m, 4 H), 7.65–7.57 (m, 3 H),
7.36 (m, 2 H), 7.29 (m, 2 H), 7.20–7.14 (m, 4 H), 5.57 (d, 3J =
2.7 Hz, 1 H, H-9), 3.60 (m, 1 H), 2.97 (m, 1 H), 2.78 (m, 1 H), 2.56
(m, 1 H), 2.24–2.21 (m, 1 H), 1.80–1.72 (m, 2 H), 1.69–1.63 (m, 1
H), 1.52–1.47 (m, 1 H), 1.41–1.34 (m, 1 H), 1.29–1.20 (m, 1 H),
1.18–1.05 (m, 3 H), 0.94–0.89 (m, 1 H), 0.55 (s, 3 H) ppm. 13C
NMR (CDCl3/CD3OD, 1:2): δ = 151.09, 150.07, 147.92, 138.28,
137.37, 135.22, 134.84, 134.62 (2 C), 133.82, 130.64, 129.85, 129.65,
129.47, 129.33, 128.71, 128.23 (2 C), 127.43, 126.09, 125.90, 125.72,
125.35, 123.47, 118.81, 71.27, 60.40, 59.00, 43.62, 38.85, 29.05,
28.16, 25.50, 20.18, 13.11, –2.65 ppm. [α]2D4 = –55.7 (c = 0.027 m in
CHCl3). M.p. 205–207 °C. HRMS: calcd. for C36H38N2OSi
542.2753; found 542.2750. C36H38N2OSi (542.79): calcd. C 79.66,
H 7.06, N 5.16; found C 79.21, H 6.84, N 5.14.
3
1H NMR (CDCl3): δ = 8.73 (d, J2Ј,3Ј = 4.5 Hz, 1 H, H-2Ј), 8.07
(dd, 4J8Ј,6Ј = 1.2, 3J8Ј,7Ј = 8.5 Hz, 1 H, H-8Ј), 7.86 (dd, 4J5Ј,7Ј = 1.3,
4
3
3J5Ј,6Ј = 8.5 Hz, 1 H, H-5Ј), 7.60 (ddd, J7Ј,5Ј = 1.3, J7Ј,6Ј = 6.8,
3J7Ј,8Ј = 8.5 Hz, 1 H, H-7Ј), 7.48 (d, J3Ј,2Ј = 4.5 Hz, 1 H, H-3Ј),
3
7.39 (m, 6 H, o-H), 7.32 (m, 1 H, H-6Ј), 7.29 (m, 3 H, p-H), 7.22
(m, 6 H, m-H) 5.55 (d, 3J9,8 = 3.8 Hz, 1 H, H-9), 4.79 (s, 1 H, OH),
3
2
3.43 (m, 1 H, H-6b), 2,94 (dd, J2a,3 = 9.8, J2a,2b = 13.5 Hz, 1 H,
H-2a), 2.88 (m, 1 H, H-8), 2.50 (m, 1 H, H-6a), 2.26 (dm, 1 H, H-
2b), 1.79 (m, H-4), 1.73–1.63 (m, 2 H, H-5b, H-7b), 1.47–1.40 (m,
H, H-3), 1.38–1.28 (m, 2 H, H-10), 1.29–1.24 (m, 2 H, H-5a, H-
7a), 1.23–1.18 (m, 2 H, H-11) ppm. 13C NMR (CDCl3): δ = 149.99
(C-2Ј), 149.62 (C-4Ј), 148.09 (C-8aЈ), 135.45 (6 C, o-C), 134.90 (3
C, i-C), 130.12 (C-8Ј), 129.38 (3 C, p-C), 128.93 (C-7Ј), 127.77 (6
C, m-C), 126.53 (C-6Ј), 125.61 (C-4aЈ), 122.96 (C-5Ј), 118.18 (C-
3Ј), 71.77 (C-9), 60.07 (C-8), 58.53 (C-2), 43.28 (C-6), 38.80 (C-3),
1,2-Bis[(10,11-dihydrocinchonidin-11-yl)dimethylsilyl]ethane (4d): To
a solution of 2 (1.45 g, ca. 3.6 mmol of pure substance) in toluene
2818
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2811–2821

Synthesis of Chiral Catalyst Modifiers by Hydrosilylation of Cinchonidine
FULL PAPER
(5 mL) was added one drop of Karstedt’s catalyst. After stirring at
room temperature for 15 min, 1,2-bis(dimethylsilyl)ethane (0.26 g,
1.8 mmol) was added. The reaction mixture was stirred at 80–90 °C
for 3 h. After cooling to room temperature, the solvent was evapo-
rated and the residue purified by gradient flash chromatography
(CH2Cl2/MeOH, 20:1 Ǟ 10:1) to yield 0.62 g (0.7 mmol, 40%) of
1,2-bis{[9-O-(trimethylsilyl)-10,11-dihydrocinchonidin-11-yl]di-
atoms with the fixed isotropic displacement parameters. Figure 2
was drawn with Ortep-3 for Windows.[32] Crystal data for 4b:
C37H38N2OSi, Mr = 554.78, orthorhombic, a = 9.1075(3), b =
16.5504(6), c = 20.4958(4) Å, V = 3089.39(16) Å3, T = 173 K, space
group P212121 (no. 19), Z = 4, μ(Mo-Kα) = 0.108 mm–1, dc
=
1.193 Mg/m3, Flack’s parameter = 0.15(13), 5119 unique reflec-
tions, which all were used in the calculations. The final R values
methylsilyl}ethane (3d) as a white solid. 1H NMR (CDCl3): δ = were R1 = 0.0506, wR2 = 0.1223 (all data) with I Ͼ 2σ(I). The
3
4
3
8.87 (d, J2Ј,3Ј = 4.4 Hz, 2 H, H-2Ј), 8.13 (dd, J8Ј,6Ј = 1.2, J8Ј,7Ј
=
ratio of reflections/parameter was 13.7. CCDC-257974 contains the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
4
8.5 Hz, 2 H, H-8Ј), 8.10 (br., 2 H, H-5Ј), 7.70 (ddd, J7Ј,5Ј = 1.3,
3J7Ј,6Ј = 6.8, J7Ј,8Ј = 8.5 Hz, 2 H, H-7Ј), 7.55 (ddd, J6Ј,8Ј = 1.2,
3
4
3J6Ј,7Ј = 6.8, J6Ј,5Ј = 8.4 Hz, 2 H, H-6Ј), 7.49 (br., 2 H, H-3Ј), 5.63 Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
3
3
2
(br., 2 H, H-9), 3.38 (br., 2 H, H-6b), 3,05 (dd, J2a,3 = 9.9, J2a,2b
= 13.4 Hz, 2 H, H-2a), 2.95 (br., 2 H, H-8), 2.64 (m, 2 H, H-6a),
2.26 (m, 2 H, H-2b), 1.79–1.68 (m, 6 H, H-4, H-5b, H-7b), 1.44–
1.34 (m, 6 H, H-3, H-5a, H-7a), 1.15–1.06 (m, 4 H, H-10), 0.34–
0.29 (m, 4 H, H-11), 0.20 (s, 4 H, H-13), 0.03 (s, 18 H, Si–CH3),
–0.22 (s, 12 H, H-14) ppm. 13C NMR (CDCl3): δ = 150.00 (C-2Ј),
149.58 (C-4Ј), 148.47 (C-8aЈ), 130.45 (C-8Ј), 128.95 (C-7Ј), 126.57
(C-6Ј), 125.56 (C-4aЈ), 123.22 (C-5Ј), 118.75 (C-3Ј), 73.13 (C-9),
61.45 (C-8), 59.08 (C-2), 43.22 (C-6), 39.29 (C-3), 28.59 (2 C, C-5,
C-10), 25.62 (C-4), 20.91 (C-7), 9.08 (C-11), 7.43 (3 C, SiCH2CH3),
3.25 (3 C, SiCH2CH3), 0.24 (3 C, SiCH3) ppm. [α]2D4 = –95.4 (c =
0.0177 m in CHCl3). HRMS: calcd. for C50H78N4O2Si4 878.5202;
found 878.5199. C50H78N4O2Si4 (879.52): calcd. C 68.28, H 8.94,
N 6.37; found C 67.56, H 8.87, N 6.34. Next, a solution of 3d
(0.50 g, (0.57 mmol) in methanol (25 mL) was refluxed for 5 h and
left to stand overnight. Evaporation of the solvent and subsequent
washing with pentane left 0.29 g (0.4 mmol, 70%) of 4d as an ana-
Catalytic Hydrogenation: According to the standard procedure, the
5 wt-% Pt/Al2O3 catalyst (Strem Chemicals) was pre-reduced in a
fixed-bed reactor by flushing with argon (50 cm3/min) at room tem-
perature for 3 min, followed by reductive treatment in H2 (50 cm3/
min) at 400 °C for 2 h. After cooling to room temperature in hydro-
gen flow, the catalyst was flushed with argon for 30 min and was
stored under air before use [BET specific surface area 95 m2 g–1,
mean metal particle size 8.3 nm (XRD), dispersion 40% (H2 chemi-
sorption), mean catalyst particle size 18.2 μm (Malvern)]. Catalyst
characterization has been described in detail previously.[14a] The re-
duced catalyst (100 mg for 1-phenylpropane-1,2-dione hydrogena-
tion and 50 mg in the ethyl pyruvate case) together with a solution
of the chiral modifier (3.4×10–5 mol in 50 mL of toluene, corre-
sponding to 10 mg of cinchonidine) were placed in a batch reactor
(Parr, 300 cm3) and flushed with hydrogen at 1 bar for 10 min. The
reactant solution (5 mmol of 1-phenylpropane-1,2-dione or
10 mmol of ethyl pyruvate in 50 mL of toluene) was saturated with
hydrogen for 10 min in a separate injection chamber and injected
into the reactor after which the reaction was commenced immedi-
ately by starting the agitation. The reactions were carried out under
the hydrogen (AGA, 99.999%) pressure of 10 bar, reactor tempera-
ture of 15 °C and stirring rate of 2000 rpm. The initial concentra-
tions for cinchonidine and modifiers 4a–c were 3.4×10–4 mol·dm–3
(1.7×10–4 mol·dm–3 for modifier 4d) and 0.05 mol·dm–3 of 1-phen-
ylpropane-1,2-dione or 0.1 mol·dm–3 of ethyl pyruvate. The conver-
sion, chemo-, and enantioselectivity of the hydrogenation products
were determined with a Varian 3300 Gas Chromatograph (GC)
equipped with a chiral column (β-Dex 225). Details of the analyti-
cal procedure, calibration and GC standard synthesis have been
described in detail previously.[14b,25]
1
3
lytically pure white solid. H NMR (CDCl3): δ = 8.77 (d, J2Ј,3Ј
4.6 Hz, 2 H, H-2Ј), 8.13 (dd, J5Ј,7Ј = 1.3, J5Ј,6Ј = 8.5 Hz, 2 H, H-
=
4
3
4
3
5Ј), 8.03 (dd, J8Ј,6Ј = 1.2, J8Ј,7Ј = 8.5 Hz, 2 H, H-8Ј), 7.70 (ddd,
4J7Ј,5Ј = 1.3, J7Ј,6Ј = 6.8, 3J7Ј,8Ј = 8.5 Hz, 2 H, H-7Ј), 7.67 (d, 3J3Ј,2Ј
= 4.6 Hz, 2 H, H-3Ј), 7.59 (ddd, J6Ј,8Ј = 1.2, J6Ј,7Ј = 6.8, J6Ј,5Ј
8.5 Hz, 2 H, H-6Ј), 5.61 (d, J9,8 = 3.3 Hz, 2 H, H-9), 3.58 (m, 2
3
4
3
3
=
3
3
2
H, H-6b), 3,06 (dd, J2a,3 = 10.1, J2a,2b = 13.5 Hz, 2 H, H-2a),
3.00 (m, 2 H, H-8), 2.62 (m, 2 H, H-6a), 2.30 (dm, 2 H, H-2b),
1.87–1.77 (m, 6 H, H-4, H-5b, H-7b), 1.48–1.40 (m, 4 H, H-3, H-
5a), 1.31 (m, 2 H, H-7a), 1.13–1.07 (m, 4 H, H-10), 0.33–0.28 (m,
4 H, H-11), 0.17 (s, 4 H, H-13), –0.27 (s, 12 H, H-14) ppm. 13C
NMR (CDCl3): δ = 150.30 (C-4Ј), 148.92 (C-2Ј), 146.85 (C-8aЈ),
128.80 (C-7Ј), 128.39 (C-8Ј), 126.35 (C-6Ј), 125.17 (C-4aЈ), 122.54
(C-5Ј), 117.86 (C-3Ј), 70.34 (C-9), 59.66 (C-8), 57.90 (C-2), 42.43
(C-6), 37.99 (C-3), 27.94 (C-10), 27.13 (C-5), 24.63 (C-4), 19.73 (C-
7), 11.47 (C-11) 6.21 (C-13), –5.20 (C-14) ppm. [α]2D4 not determined
due to insolubility of 4d in CHCl3 and alcohols. M.p. 250–255 °C
(with decomposition). HRMS: calcd. for C44H62N4O2Si2 734.4411;
found 734.4371. C44H62N4O2Si2 (735.16): calcd. C 71.89, H 8.50,
N 7.62; found C 71.10, H 8.32, N 7.52.
Definition of Selectivities: Enantiomeric excess (ee) is defined as
([R] – [S]) × 100/([R] + [S]):
The enantiomeric excess ee(RS) is defined in an analogous manner
using concentrations of (1R,2S) and (1S,2R). The diol selectivity
Si [e.g., (1S,2R)-diol] has been defined accordingly:
X-ray Crystallographic Study of 4b: Suitable crystals of 4b for X-
ray measurements were grown from a methanol solution. The sin-
gle crystal data were collected at 173 K with a Nonius KappaCCD
area detector diffractometer using graphite-monochromatised Mo-
Kα radiation (λ = 0.71073 Å). The data collection was performed
using φ and ω scans (θ range from 2.45 to 24.71°). The data were
processed using DENZO-SMN v0.93.0.[30] The structure was
solved by direct methods using the SHELXS programme.[31] Full-
matrix least-squares refinements on F2 were performed using the
SHELXL-97 programme.[31] Non-hydrogen atoms were refined
with anisotropic displacement parameters and the OH hydrogen
atom was refined isotopically with fixed isotropic displacement
parameters. The rest of the hydrogen atoms were included in the
calculations in a riding mode at the fixed distances from their host
The regioselectivity (rs) is given by:
Eur. J. Org. Chem. 2005, 2811–2821
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2819

I. Busygin, E. Toukoniitty, R. Sillanpää, D. Yu. Murzin, R. Leino
FULL PAPER
1993, 144, 569–578; c) H. U. Blaser, D. Imhof, M. Studer, Stud.
Surf. Sci. Catal. 1997, 108, 175–182; d) M. Bartok, K. Balaz-
sik, T. Bartok, Z. Kele, Catal. Lett. 2003, 87, 235–240.
Acknowledgments
Financial support from the Academy of Finland (Project No.
201207: New modifiers for the production of enantiopure com-
pounds) and the generous support from the Magnus Ehrnrooth
foundation is gratefully acknowledged. This work has been carried
out in collaboration with the Åbo Akademi Process Chemistry
Centre within the Finnish Centre of Excellence Programme (2000–
2005) by the Academy of Finland. We also thank Mr. Markku
Reunanen for his assistance with the HRMS analyses, Dr. Rainer
Sjöholm for recording some of the NMR spectra reported in this
work and Ms. Elise Johansson for preparation of the chiral
(+)-(R)-methyl(1-naphthyl)phenylsilane. Antti Pohjakallio and
Dr. Petri Pihko at the Helsinki University of Technology
are thanked for their assistance with some of the elemental
analyses.
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www.eurjoc.org
Eur. J. Org. Chem. 2005, 2811–2821

Synthesis of Chiral Catalyst Modifiers by Hydrosilylation of Cinchonidine
FULL PAPER
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2821