Immobilization of catalysts derived from Cinchona alkaloids on modified poly(ethylene glycol)

Article abstract of DOI:10.1016/S0957-4166(02)00830-3

The straightforward immobilization of some derivatives of Cinchona alkaloids on modified poly(ethylene glycol)s is reported. The compounds, obtained by simple reactions exploiting different sites for the attachment of the alkaloids to the polymer, were te

Full text of DOI:10.1016/S0957-4166(02)00830-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 461–467
Immobilization of catalysts derived from Cinchona alkaloids on
modified poly(ethylene glycol)
a
a,c
a,c,
a,b,c
a,b,c
Tamara Danelli, Rita Annunziata, Maurizio Benaglia, * Mauro Cinquini,
Franco Cozzi
d
and Graziella Tocco
a
Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano, Via Golgi 19, I-20133 Milano, Italy
b
CNR-ISTM, Universita’ degli Studi di Milano, Via Golgi 19, I-20133 Milano, Italy
c
Centro di Eccellenza CISI, Universita’ degli Studi di Milano, Via Golgi 19, I-20133 Milano, Italy
d
Dipartimento Farmaco Chimico Tecnologico, Universita’ degli Studi di Cagliari, via Ospedale 72, I-09124 Cagliari, Italy
Received 14 November 2002; accepted 4 December 2002
Abstract—The straightforward immobilization of some derivatives of Cinchona alkaloids on modified poly(ethylene glycol)s is
reported. The compounds, obtained by simple reactions exploiting different sites for the attachment of the alkaloids to the polymer,
were tested as catalysts in the enantioselective benzylation of the benzophenone imine of glycine t-butyl ester (ee up to 64%) and
in the conjugate addition of thiophenol to cyclohexenone (ee 22%). The observed stereoselectivities were compared to those obtained
either with the unsupported catalysts or with the catalysts immobilized on different polymeric matrixes. The influence of the
poly(ethylene glycol) moieties on the catalytic activity is discussed. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
PEG-supported Cinchona alkaloids, and their use in
asymmetric catalytic processes.
Over the last 25 years chiral ligands and catalysts
derived from Cinchona alkaloids have been used to
perform a variety of fundamental organic reactions in
2. Results and discussion
1
an enantioselective fashion. With the aim of improving
the efficiency of these catalytic processes by making the
ligands and catalysts readily recoverable and recy-
clable, considerable efforts have been devoted to the
The monomethyl ether of PEG of MW 55000 Daltons
,13
(MeOPEG) was selected as the support.
This inex-
2
pensive, readily functionalized, and commercially avail-
able polymer offers distinctive advantages over other
supports because it is readily soluble in many organic
solvents and insoluble in a few other solvents. Exploit-
ing this property, one can run a reaction under homo-
geneous catalysis conditions (where the chiral catalyst is
expected to perform at its best) and recover the catalyst
as if it were bound to an insoluble matrix. In addition,
PEG has been shown to be a relatively inert support,
interfering minimally or not-at-all with the chemical
and stereochemical course of stereoselective processes
immobilization of Cinchona alkaloids on polymer sup-
ports. In this context, two main strategies have been3
followed, exploiting either insoluble organic polymers,
4
or inorganic matrixes (mostly silica gel). Soluble sup-
5
ports have been used much less frequently. In particu-
6
7
lar, Bolm and Janda reported the immobilization of
modified quinine and quinidine on poly(ethylene glycol)
(
PEG) to afford very efficient and recoverable ligands
for the Sharpless’ asymmetric dihydroxylation reaction.
To the best of our knowledge, however, no examples of
Cinchona catalysts supported on soluble polymers have
been described. As part of a project
immobilization of organic (i.e. metal free) catalysts on
soluble polymers, we report herein the synthesis of
5
promoted by PEG-supported catalysts. Moreover, cat-
8
–11
alyst recovery and recycling is possible for at least a few
devoted to the
8–11
12
reaction cycles,
with the metal-free nature of the
catalysts greatly facilitating this procedure since metal
re-loading, often required in metal-catalyzed reac-
6,7,14
tions,
is not necessary.
On the basis of our previous experience in this field,
two activated derivatives of MeOPEG, namely mesylate
1
and bromide 2 (Scheme 1) were employed to support
*
0
Corresponding author. Tel.: +39/02/50314171; fax: +39/02/
0314159; e-mail: maurizio.benaglia@unimi.it
5
the catalysts. They were easily obtained in ]95% yield
957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00830-3

4
62
T. Danelli et al. / Tetrahedron: Asymmetry 14 (2003) 461–467
Scheme 1. Synthesis of supported catalysts 6–9.
8
,15
from MeOPEG as previously described
and featured
quinidine could provide another reactive site for selec-
good leaving groups to facilitate alkaloid attachment
via nucleophilic displacement.
tive attachment. Accordingly, 6%-hydroxycinchonine (6%-
16
norquinine) 3 was synthesized following a known
procedure and, from this, quaternary ammonium salt 4
1
7
was obtained in 81% yield by alkylation with 9-
(chloromethyl)anthracene in toluene (Scheme 1).
So far, Cinchona alkaloids have been immobilized
exploiting three different sites of attachment, namely
1
the most commonly used vinyl residue (employed for
6
,7
Reaction of the caesium salt of compound 3 with
instance in combination with MeOPEG), the benzyl-
type oxygen at C-9 (Cinchona alkaloids’ numbering),
and the less frequently employed bridgehead nitrogen
of the quinuclidine residue. We reasoned that demethyl-
ation of the methoxy group at C-6% of quinine and
mesylate 1 (DMF, 50–60°C, 40 h) afforded adduct 6 in
†
9
0% isolated yield. Since relevant enantioselective pro-
†
For a detailed description of yield and purity determination for
PEG-supported compounds, see Section 4.

T. Danelli et al. / Tetrahedron: Asymmetry 14 (2003) 461–467
463
cesses involve Cinchona alkaloid catalysts featuring an
tions with solid CsOH as the base, −78°C, 23 h) and
18,19
22
ester residue at C-9,
compound 6 was transformed
Lygo (91% ee under liquid/liquid conditions with 50%
into the benzoate 7 by reaction with benzoyl chloride
aqueous KOH as the base, rt, 18 h). The results
obtained with the same loading of catalysts 8 and 9
(10% mol) are collected in Table 1. The yields were
‡
and trioctylamine in DCM (83% yield). This com-
pound was also involved in the preparation of catalysts
20,21
1
for enantioselective fluorination reactions.
Reaction
determined by H NMR analysis of the crude product
of ammonium salt 4 with mesylate 1 under the same
conditions employed for the synthesis of 6 afforded
adduct 8 in 75% yield.
and confirmed by HPLC on a chiral stationary phase
while assessing the ee; the absolute configuration of the
product was assigned by comparison of HPLC profiles
with that of a sample of (S)-10 of known absolute
configuration.
Finally, a DCM solution of the commercially available
N-(9-anthracenylmethyl)cinchonidinium chloride 5 (1.2
mol equiv.) and bromide 2 in the presence of a 50%
w/w aqueous solution of KOH (rt, 72 h) gave the
supported ammonium salt 9 in 70% yield.
As can be seen from the reported data, the supported
catalysts 8 and 9 promoted the formation of compound
1
0 in ee lower than those observed when the reaction
was carried out with catalyst 5. In particular, the
quininium catalyst 8 performed less well than the cin-
chonidinium analog 9 (entry 1 versus 8 and 5 versus 9,
Table 1). The latter, therefore, was used for most of the
experiments. The difference in behavior of the two
catalysts, expected on the basis of previous
observations although not to the dramatic extent
observed here, suggested that the introduction of the
polymer chain affected 8 more strongly than 9.
It must be noted that the synthesis of 8 and 9 released
a mesylate and a bromide ion, respectively. These can
compete with the pre-existing chloride ion in neutraliz-
ing the positive charge at the bridgehead nitrogen.
1
While H NMR analysis allowed to rule out a chloride/
23
mesylate exchange in compound 8, no evidence was
collected about the counterion nature in adduct 9, that
might either be chloride or bromide.
When the same base was used, solid/liquid conditions
gave higher ee than liquid/liquid conditions (entry 3
versus 1). The use of solid CsOH instead of solid KOH
improved the ee (entry 7 versus 4). Low reaction tem-
peratures were beneficial for the ee but not for the
chemical yield (entry 7 versus 6 versus 5). Under the
best conditions (entry 7), a maximum ee of 64% was
observed for the product obtained in 75% yield.
The supported catalysts 8 and 9 were then tested under
different conditions in the enantioselective benzylation
of the N-benzophenone imine derived from glycine
t-butyl ester (Fig. 1) to afford the corresponding (S)-
phenylalanine precursor 10. This reaction has been
shown to occur with excellent levels of enantiomeric
17
excess (ee) by Corey (94% ee under solid/liquid condi-
Among the factors that can explain why the enantiose-
lectivities observed here were lower than those obtained
17,22
with the unsupported catalysts,
the involvement of
the PEG portion of catalysts 8 and 9 seems the most
likely. We believe that PEG can influence the steric
course of the reaction essentially exerting two effects:
Firstly, by increasing the polarity of the organic phase,
PEG in part prevents the formation of a tight ion pair
Figure 1. Synthesis of adduct (S)-10.
Table 1. Enantioselective benzylation of the benzophenone imine of glycine t-butyl ester catalyzed by compounds 8 and 9
under different conditions
Entry
Catalyst
Base
T (°C); time (h)
Yield (%)a
Ee (%)b
1
2
3
4
5
6
7
8
9
9
9
9
9
9
9
9
8
8
50% aq. KOH
10% aq. KOH
Solid KOH
23; 20
23; 20
23; 20
−78; 60
−78 to 23; 22
−78 to −5; 22
−78; 60
23; 20
−78 to 23; 22
93
65
85
80
92
86
75
90
94
30
18
40
58
30
46
64
8
Solid KOH
Solid CsOH
Solid CsOH
Solid CsOH
50% aq. KOH
Solid CsOH
12
a
Determined by 1H NMR and HPLC on the crude product. The only contaminant was the starting material.
Determined by HPLC on a chiral stationary phase.
b
‡
The use of trioctylamine instead of other bases (e.g. TEA, DIPEA) as HCl scavenger in this reaction greatly simplified the isolation of pure
PEG-supported compounds (see Ref. 15).

4
64
T. Danelli et al. / Tetrahedron: Asymmetry 14 (2003) 461–467
between the enolate and the chiral ammonium salt (a
factor regarded as crucial for achieving high stereocon-
trol). Secondly, PEG enhances the solubility of the
inorganic cation in the organic phase leading to com-
peting nonstereoselective alkylation occurring on an
achiral caesium or potassium enolate rather than the
chiral ammonium enolate of the substrate.
recovery, and recycling of the catalyst was reported.
This high ee value has not been surpassed by the use of
other insoluble-polymer supported catalysts related to
5, where the bridgehead nitrogen was employed for
1
7
25,26
polymer attachment.
Since some of these catalysts
25
could be recycled, they appear to be stable.
The conjugate addition of thiophenol to cyclohexenone
to afford adduct (R)-11 (Fig. 2) carried out in the
presence of 6 (5% mol) was studied to test the behavior
of a neutral supported catalyst. After 24 h reaction in
toluene (a solvent in which the PEG-derivative is solu-
ble at rt) the product was obtained in 75% yield and
To establish the influence of PEG, control experiments
were performed by running the reaction with unsup-
ported catalyst 5 in the presence of the bismethyl ether
of PEG having MW 2000 Daltons. Under the condi-
tions of entries 1 and 7 compound 10 was obtained in
2
2% ee, as determined by comparison of its specific
76 and 65% ee, respectively. The almost perfect coinci-
rotation value. The obtained ee was lower than that
observed by Wynberg and Hiemstra in the same reac-
tion catalyzed by 1% molar of non supported quinine
dence of the ee obtained under solid/liquid conditions
with catalyst 5 in the presence of PEG (65%) and with
catalyst 9 (64%) seems to indicate that the above-men-
tioned solubilizing effect of the inorganic cation in
organic solution can indeed be a negative factor in the
reaction promoted by the supported catalyst. In this
respect, it is also worth mentioning that the PEG-por-
tion of achiral PEG-supported phase transfer
27
(
ee=41%). The possibility that the PEG backbone
can, at least in part, prevent the formation of the
hydrogen bonding between the catalyst and cyclo-
hexenone (a mechanistic factor regarded as relevant to
27
secure a stereoselective addition reaction ) can tenta-
tively rationalize the decrease in the ee of adduct 11. It
is interesting to note, however, that the ee obtained
with the PEG-supported catalyst 6 was slightly higher
than that observed in a very similar reaction (addition
of 4-methylthiophenol to cyclohexenone) with quinine
immobilized on insoluble polystyrene as the catalyst
8
,10
catalysts
was shown to have very limited catalytic
ability itself, but strongly enhanced that of a PEG-sup-
8,10
ported catalyst in base-promoted alkylations.
Recycling of the supported catalyst 9 was then studied:
The catalyst was recovered from the reaction (entry 7)
by evaporation of the solvent and addition of diethyl
ether. In this solvent the unsupported materials were
readily soluble while the insoluble catalyst was isolated
2
8
(
ee=18% under the same reaction conditions).
1
by filtration. However, H NMR analysis showed that
the recovered material was largely decomposed. A lib-
eral estimate indicated that 9 represented no more than
5
0% of the recovered mixture. It was not surprising,
therefore, that when this material was used to catalyze
a second reaction run described in Fig. 1 (carried out
under the conditions of entry 7) product 10 was isolated
in only 11% yield and 30% ee. Repetition of this
experiment after addition of fresh CsOH improved the
yield of 10 to 70% but the ee was lowered to 25%.
Figure 2. Synthesis of adduct (R)-11.
3
. Conclusions
In conclusion, some derivatives of Cinchona alkaloids
were supported on modified poly(ethylene glycol)s by
simple reactions and exploiting different sites of attach-
ment for the polymer. The resulting species were
employed as catalysts in the enantioselective benzyla-
tion of the benzophenone imine of glycine t-butyl ester
In order to establish if the instability of the catalyst was
due to the presence of PEG, the reaction (Fig. 1 was
repeated at −78°C for 20 h with catalyst 5 and with
1
5
/PEG (see above). H NMR analysis of the catalyst
recovered from both these reactions showed that exten-
sive catalyst decomposition occurred, independently of
the presence of PEG, as shown by the appearance, inter
alia, of peaks at l 9.80, 9.05, 8.60, 8.25, 6.15, 5.20 ppm.
These experiments suggested that the unsupported cata-
lyst was intrinsically unstable and such remained when
supported on PEG.
(
ee up to 64%) and in the conjugate addition of thio-
phenol to cyclohexenone (ee 22%). Tentative explana-
tions for the fact that the observed stereoselectivities
were lower than those obtained with the unsupported
catalysts have been proposed.
4
. Experimental
The results obtained in the synthesis of 10 with catalyst
9
can be compared to those observed under very similar
4.1. General
conditions (entry 7) with the catalyst prepared by
24
1
Plaquevent and Cahard by immobilization of 5 on
insoluble Merrifield resin by means of an ether bond,
also involving the benzyl-type oxygen. With this insolu-
ble catalyst product 10 was isolated in 67% yield and
H NMR spectra were recorded at 300 MHz and were
13
referenced to tetramethylsilane (TMS) at 0.00 ppm.
C
NMR spectra were recorded at 75 MHz and were
referenced to 77.0 ppm in chloroform-d (CDCl ). Opti-
cal rotations were measured at the Na-D line in a 1 dm
3
94% ee. Unfortunately, no mention of the stability,

T. Danelli et al. / Tetrahedron: Asymmetry 14 (2003) 461–467
465
cell at 22°C. IR spectra were recorded on thin film or as
solution in CH Cl . 1, 2, 3, the benzophenone imine of
of N-CH CH ), 4.00 (d, 1H, J=13.0 Hz, one H of
2 2
N-CH –CH-vinyl), 2.68 (t, 1H, J=12.0 Hz, one H of
2
2
2
2
9
17
t-butyl glycinate, and 10 are known compounds; 5 is
N-CH –CH-vinyl), 2.27 (m, 1H, N-CH CH ), 2.18 (m,
2
2
2
commercially available.
1H, H-C-vinyl), 1.73 (m, 3H, bridgehead CH and one
H of both CH bound to this C), 1.07 (m, 2H, one H of
2
All PEG samples were melted at 80°C in vacuum for 30
min before use to remove traces of moisture. After
reaction PEG-supported product purification involved
evaporation of the reaction solvent in vacuum and
addition of the residue dissolved in a few mL of CH Cl
to diethylether (50 mL g of polymer), which was
stirred and cooled at 0°C. After 20–30 min stirring at
both CH bound to the bridgehead C). C H ClN O
2
34 33
2
2
requires: C, 76.03; H, 6.19; N, 5.22. Found: C, 75.88;
H, 6.02; N, 5.08%.
2
2
4
.4. General procedure for the synthesis of adducts 6
−
1
and 8 from mesylate, 1
0
°C, the obtained suspension was filtered through a
sintered glass filter, and the solid repeatedly washed on
the filter with diethylether (up to 100 mL per gram of
polymer, overall).
4
.2. Yield and purity determination of PEG-supported
compounds
The yields of the PEG-supported compounds were
determined by weight with the assumption that M is
5
ranged from 4500 to 5500. The indicated yields were for
pure compounds. The purity of these compounds was
determined by H NMR analysis in CDCl at 300 MHz
with pre-saturation of the methylene signals of the
polymer at l=3.63. In recording the NMR spectra, a
relaxation time of 6 s and an acquisition time of 4 s
were used to ensure complete relaxation and accuracy
of the integration. The relaxation delay was selected
after T measurements. The integration of the signals of
the PEG CH OCH fragment at l=3.30 and 3.36 were
w
000 Da for the PEG fragment. The Mw actually
1
3
1
2
3
used as internal standard. The estimated integration
error was +5%.
anthracenyl-CH ), 4.10 (m, 5H, PEGCH OPh, CH O-
2
2
2
4
.3. N-(9-Anthracenylmethyl)-6%-hydroxycinchoninium
quinoline, and CH-OH), 3.87 (t, 2H, J=6.7 Hz,
PEGOCH CH OPh), 3.36 (s, 3H, MeOPEG), 3.00–2.50
chloride, 4
2
2
(
m, 4H, H close to N in quinuclidine), 2.80 (t, 2H,
To a suspension of compound 3 (0.310 g, 1 mmol) in
dry toluene (5 mL) stirred at 100°C, 9-anthracenyl-
methyl chloride (0.238 g, 1.05 mmol) was added in one
portion. After 20 h stirring at 100°C, the mixture was
cooled at rt and poured into diethylether (10 mL). The
precipitate was filtered and washed with diethylether to
J=7.8 Hz, PhCH ), 2.46 (m, 1H, CH-vinyl), 2.33 (m,
2
1
H, other H close to N in quinuclidine), 2.17 (m, 2H,
CH CH CH ), 1.90–1.50 (m, 5H, remaining H of
2
2
2
quinuclidine).
afford a pale yellow solid (0.434 g, 81% yield). Mp
4.4.1. Compound 6. Compound 6 was obtained in 90%
1
1
60°C (dec.); [h]=−320.7 (c 0.3, chloroform).
H
yield by a similar procedure to that shown above.
1
NMR: l 9.25 (bs, 1H, ArOH), 9.08 (d, 1H, J=9.0 Hz,
H-C1 of anthracenyl), 8.75 (d, 1H, J=4.5 Hz, H-C2 of
quinoline), 8.46 (d, 1H, J=9.2 Hz, H-C7 of anthra-
cenyl), 8.15 (d, 1H, J=2.1 Hz, H-C5 of quinoline), 7.97
[h]=−3.7 (c 0.15, chloroform). H NMR: l 8.75 (d, 1H,
J=4.5 Hz, H-C2 of quinoline), 8.03 (d, 1H, J=9.0 Hz,
H-C8 of quinoline), 7.53 (d, 1H, J=4.5 Hz, H-C3 of
quinoline), 7.38 (d, 1H, J=9.0 Hz, H-C8 of quinoline),
7.28 (s, 1H, H-C5 of quinoline), 7.13 (B part of AB
system, 2H, J=8.4 Hz, H meta to O in PEG-O-Ph),
6.84 (A part of AB system, 2H, J=8.4 Hz, H ortho to
(
s, 1H, H-C10 of anthracenyl), 7.88 (d, 1H, J=4.5 Hz,
H-C3 of quinoline), 7.64 (d, 1H, J=8.2 Hz, H-C4 of
anthracenyl), 7.58 (m, 2H, H-C8 of quinoline and H-C5
of anthracenyl), 7.47 (bd, 1H, J=3.8 Hz, quinoline-
CH-OH), 7.40 (t, 1H, J=7.8 Hz, H-C2 of anthracenyl),
O in PEG-O-Ph), 5.83 (m, 1H, CH=CH ), 5.45 (d, 1H,
2
J=5.0 Hz, CH-OH), 4.92 (m, 2H, CH=CH ), 4.10 (m,
2
7
1
.26 (m, 2H, H-C7 and H-C3 of anthracenyl), 7.08 (t,
H, J=7.4 Hz, H-C6 of anthracenyl), 6,78 (m, 2H,
4H, PEGCH OPh and CH O-quinoline), 3.87 (t, 2H,
2
2
J=6.7 Hz, PEGOCH CH OPh), 3.36 (s, 3H,
2 2
quinoline–CH-OH and H-C7 of quinoline), 6.49 (B
part of AB system, 1H, J=15.7 Hz, one H of anthra-
MeOPEG), 3.30 (m, 2H, MeO CH ), 3.10–2.50 (m, 5H,
2
H close to N in quinuclidine), 2.80 (t, 2H, J=7.8 Hz,
cene-CH ), 6.39 (A part of AB system, 1H, J=15.7 Hz,
PhCH ), 2.26 (m, 1H, CH-vinyl), 2.10 (m, 2H,
2
2
one H of anthracene-CH ), 5.34 (m, 2H, CHꢀCHH),
CH CH CH ), 1.90–1.50 (m, 5H, remaining H of
2
2
2
2
4.99 (d, 1H, CHHꢀ), 4.62 (m, 2H, HC-COH and one H
quinuclidine).

4
66
T. Danelli et al. / Tetrahedron: Asymmetry 14 (2003) 461–467
4
.5. Benzoylation of compound 6 to give ester, 7
in the phenyl rings of the spacer), 6.82 (m, 4H, H
ortho to O in the phenyl rings of the spacer), 6.10 (m,
+
To a stirred solution of compound 6 (0.525 g, 0.093
mmol) and trioctylamine (0.082 mL, 0.186 mmol) in
DCM (3 mL), freshly distilled benzoyl chloride (0.017
mL, 0.140 mmol) in DCM (0.5 mL) was added. After
1H, CHꢀCH ), 5.14 (t, 1H, J=4.0 Hz, H-C-N ), 5.01
2
(m, 2H, CHꢀCH ), 4.39 (s, 2H, Ph-CH -O-CH), 4.36
(s, 2H, anthracenyl-CH ), 4.10 (m, 3H, PEGCH OPh
2
2
2
2
and CH-O), 3.90 (m, 4H, PEGOCH CH OPh and
2
2
1
5 h stirring at rt, the reaction was quenched by the
PhCH CH CH OPh), 3.36 (s, 3H, MeOPEG), 2.95–
2 2 2
addition of water (2 mL). The organic phase was
separated, the aqueous phase was extracted with DCM
2.50 (m, 5H, PhCH CH CH OPh and 3H close to
2 2 2
+
N ), 2.36–1.40 (m, 9H, PhCH CH CH OPh and
2
2
2
(
2×5 mL), and the combined organic phases were
remaining H in quinuclidine).
dried over sodium sulfate. Evaporation of the solvent
under vacuum gave a residue to which diethylether (10
mL) was added. The suspension was stirred for 30 min
and then filtered to afford the product as a pale yel-
low solid (0.443 g, 83%). [h]=+6.6 (c 0.3, chloroform).
4.7. General procedures for the synthesis of 10
4.7.1. Liquid/liquid procedure. To a stirred solution of
the imine (0.060 g, 0.2 mmol), benzyl bromide (0.031
mL, 0.26 mmol), and catalyst 9 (0.112 g, 0.02 mmol)
in dry DCM (5 mL), a 50% w/w aqueous solution of
KOH (0.5 mL) was added. The solution was vigor-
ously stirred at rt for 20 h, whereupon 2 mL of water
were added. The organic phase was separated, the
aqueous phase was washed with DCM (2×5 mL), and
the combined organic phases were dried over sodium
sulfate and concentrated under vacuum. To the
residue, diethylether (10 mL) was added to precipitate
the catalyst. This was filtered off and the filtrate was
concentrated under vacuum to give the product (93%
yield by NMR) contaminated only by the starting
imine. The ee was determined by HPLC on a Chiralcel
OD column, 99:1 hexane: 2-propanol mixture as elu-
ent, flow rate 1 mL/min, 23°C, u=254 nm: retention
time of the minor (R) isomer: 7.3 min; of the major
(S) isomer: 10 min.
1
H NMR: l 8.68 (d, 1H, J=4.5 Hz, H-C2 of quino-
line), 8.10 (d, 1H, J=9.0 Hz, H-C8 of quinoline), 8.00
(
d, 2H, J=9.0 Hz, H ortho to CꢀO), 7.54 (d, 1H,
J=4.5 Hz, H-C3 of quinoline), 7.40 (m, 4H, H-C8 of
quinoline and remaining 3 H of PhCO), 7.28 (s, 1H,
H-C5 of quinoline), 7.13 (B part of AB system, 2H,
J=8.4 Hz, H meta to O in PEG-O-Ph), 6.84 (A part
of AB system, 2H, J=8.4 Hz, H ortho to O in PEG-
O-Ph), 6.70 (d, 1H, J=6.0 Hz, CH-OCOPh), 5.85 (m,
1
H, CHꢀCH ), 5.00 (m, 2H, CHꢀCH ), 4.10 (m, 4H,
2
2
PEGCH OPh and CH O-quinoline), 3.86 (t, 2H, J=
2
2
6
3
.7 Hz, PEGOCH CH OPh), 3.36 (s, 3H, MeOPEG),
2 2
.30 (m, 2H, MeO CH ), 2.80 (t, 2H, J=7.8 Hz,
2
PhCH ), 2.70–2.50 (m, 5H, H close to N in quinu-
2
clidine), 2.32 (m, 1H, CH-vinyl), 2.17 (m, 2H,
CH CH CH ), 2.05–1.50 (m, 5H, remaining H of
2
2
2
quinuclidine).
4
.6. Synthesis of catalyst 9 from bromide, 2
4.7.2. Solid/liquid procedure. To a stirred solution of
the imine (0.060 g, 0.2 mmol), benzylbromide (0.120
mL, 1 mmol), and catalyst 9 (0.112 g, 0.02 mmol) in
dry DCM (5 mL) cooled at −78°C, CsOH monohy-
drate (0.336 g, 2 mmol) was added. The solution was
vigorously stirred at −78°C for 60 h. The mixture was
the warmed up to rt and CsOH was filtered off. The
filtrate was concentrated under vacuum. To the
residue, diethylether (10 mL) was added to precipitate
the catalyst. This was filtered off and the filtrate was
concentrated under vacuum to give the product (75%
yield by NMR) contaminated only by the starting
imine. The ee was determined by HPLC as above.
To a stirred solution of bromide 2 (2.0 g, 0.376 mmol)
in DCM (10 mL), compound 5 (0.235 g, 0.451 mmol)
and a 50% w/w aqueous solution of KOH (0.7 mL)
were added in this order. The reaction was vigorously
stirred at rt for 72 h (longer reaction times led to the
formation of by-products) and water (5 mL) was then
added. The mixture was then filtered on a Celite cake
and the filtrate was allowed to stand for a couple of
hours to obtain a satisfactory phase separation (the
time necessary for phase separation was found to
directly depend on the amount of 2 used). The organic
phase was then separated and the aqueous phase was
extracted with DCM (3×10 mL). The combined
organic phases were dried over sodium sulfate, filtered
and concentrated under vacuum to give a residue (ca.
4.8. Synthesis of adduct 11
To a stirred solution of freshly distilled thiophenol
(0.118 mL, 1.15 mmol) in dry toluene (5 mL) kept
under nitrogen, catalyst 6 (0.275 g, 0.05 mmol) was
added. After 5 min stirring at rt, cyclohexenone (0.097
mL, 1.0 mmol) in toluene (1 mL) was added and
stirring was continued for 24 h at rt. The solvent was
then evaporated under vacuum and diethylether (10
mL) was added to the residue. The precipitated cata-
lyst was removed and recovered by filtration, whereas
the filtrate was concentrated under vacuum to afford
the crude product, that was purified by flash chro-
matography with a 9:1 hexanes:EtOAc mixture as elu-
2
mL) from which the product was precipitated by
addition of diethylether. The product was then iso-
lated by filtration as a pale brown solid (1.485 g, 70%
yield). [h]=+3.3 (c 0.8, chloroform). H NMR: l 8.88
1
(
d, 1H, J=4.6 Hz, H-C2 of quinoline), 8.59 (d, 2H,
J=8.4 Hz, H-C1 and H-C8 of anthracenyl), 8.41 (s,
H, H-C10 of anthracenyl), 8.27 (d, 1H, J=8.7 Hz,
1
H-C8 of quinoline), 8.13 (d, 2H, J=8.4, H-C5 of
quinoline), 8.00 (d, 2H, J=7.6 Hz, H-C4 and H-C5 of
anthracenyl), 7.73 (t, 1H, J=7.6 Hz, H-C6 of quino-
line), 7.50 (m, 5H, H-C2, H-C3, H-C6, and H-C7 of
anthracenyl, and H-C7 of quinoline), 7.30 (d, 1H, J=
ent. Adduct (R)-11, [h]578=+21.5 (c 1.0, CCl ) was
4
4
.3 Hz, H-C3 of quinoline), 7.08 (m, 4H, H meta to O
obtained in 75% yield (0.206 g).

T. Danelli et al. / Tetrahedron: Asymmetry 14 (2003) 461–467
467
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