Recyclable copper catalysts in the enantioselective glyoxylate-ene reaction catalyzed by chiral fluorous-tagged bis(oxazolines)

Article abstract of DOI:10.1016/j.tetasy.2007.11.004

Chiral fluorous bis(oxazoline)/copper complexes have been applied to the asymmetric glyoxylate-ene reaction, giving moderate to high enantioselectivities. An efficient separation of the copper catalyst using a solid/liquid separation or the FRPSG concept,

Full text of DOI:10.1016/j.tetasy.2007.11.004

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2782–2786
Recyclable copper catalysts in the enantioselective glyoxylate-ene
reaction catalyzed by chiral fluorous-tagged bis(oxazolines)
Robert Kolodziuk, Catherine Goux-Henry and Denis Sinou*
`
´ ´
Laboratoire de Synthese Asymetrique associe au CNRS, UMR 5246-ICBMS, CPE Lyon, Universite Claude Bernard Lyon 1,
43 boulevard du 11 novembre 1918, F-69622 Villeurbanne Cedex, France
´
Received 19 September 2007; accepted 5 November 2007
Available online 28 November 2007
Abstract—Chiral fluorous bis(oxazoline)/copper complexes have been applied to the asymmetric glyoxylate-ene reaction, giving moder-
ate to high enantioselectivities. An efficient separation of the copper catalyst using a solid/liquid separation or the FRPSG concept, and
its reuse was achieved.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
fluorous catalysts could be recovered from the reaction
mixture by a simple solid/liquid separation and reused effi-
ciently.3c,6 A more promising approach is the use of FSG as
a solid support for the non-covalent immobilization of
fluorous catalysts (fluorous reverse phase silica gel or
FRPSG concept), allowing the reaction to be performed
in the usual organic solvents.4d,7 This methodology has
been successfully used in intermolecular asymmetric cyclo-
propanation and more recently in asymmetric hydrogena-
tion of olefins. The chiral catalyst can be reused in the
latter case several times with no loss of activity or enantio-
selectivity (90–95% ee).3b,8
Asymmetric organometallic catalysis is now a well used
methodology in organic synthesis.1 However, the major
drawback of such a process is the separation of the chiral
metal complexes from the product(s) of the reaction for
its recovery and/or its recycling. A very promising
approach is the use of biphasic systems,2 including aque-
ous-, ionic liquid-, and fluorous-organic biphasic (FBS)
systems, as well as catalysis in a supercritical dioxide. In
the FBS concept, the organometallic catalyst is soluble in
a fluorous solvent via the attachment of fluorous ponytails
to the ligand, and the reactants are soluble in the organic
solvent. At the end of the reaction, the two phases can be
separated, and eventually the fluorous layer containing
the fluorous organometallic catalyst can be reused. In the
literature there are only a few examples of this methodology
using chiral fluorous ligands with an efficient recycling of
the catalyst.3 Another method for the recovery of the fluor-
ous catalyst is filtration through a plug of fluorous silica gel
(FSG), called fluorous solid-phase extraction, using light
fluorous ligands;4 however, the use of this methodology
in the case of chiral fluorous ligands generally suffered from
the formation of partially inactive catalysts.5 Since chiral
fluorous organometallic species are less soluble in the usual
organic solvents in comparison to fluorous solvents, chiral
We recently described the synthesis of chiral fluorous
bis(oxazolines), which were used in palladium-catalyzed
allylic alkylation,3d,6c in CuI-promoted cyclopropanation6b
and allylic oxidation.3c,6c The recycling of the fluorous cat-
alyst was possible in some cases by using the FBS concept
or by a solid/liquid separation. Benaglia et al. reported at
around same period the synthesis of other chiral fluorous
bis(oxazolines),9 and their applications in CuI-promoted
cyclopropanation, CuII-catalyzed ene reaction, and
Mukayama aldol reaction; the recycling of the fluorous
ligand only was studied by a liquid/liquid phase separation,
or by a filtration through a short plug of fluorous silica gel.
Herein we report the use of the chiral fluorous bis(oxazo-
lines) 1a–b (Fig. 1) prepared by our group in the CuII-pro-
moted ene-type reaction, and the recycling of these chiral
fluorous organometallic catalysts using both the solid/li-
quid separation and the FRPSG concept.
*
Corresponding author. Tel.: +33 4 72 44 81 83; fax: + 33 4 78 89 89 14;
e-mail: sinou@univ-lyon1.fr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.004

R. Kolodziuk et al. / Tetrahedron: Asymmetry 18 (2007) 2782–2786
2783
a blue solid. This recovered catalyst was used for four fur-
ther cycles, affording product 2 in the same chemical yields
and enantioselectivities, up to 88% (Table 1, entry 1). We
performed an experiment under the same conditions using
the non-fluorous 2,20-isopropylidenebis(4-phenyl-2-oxazo-
line) as the chiral ligand. Evaporation of the solvent fol-
lowed by extraction with hexane gave product 2 in 88%
yield and 68% ee. However, the reuse of the brown solid
obtained by precipitation with hexane gave no reaction at
all. This blank experiment clearly showed the importance
of the fluorous ponytails for the precipitation and so the
reuse of the catalyst.
F17C8
C8F17
O
O
R
N
N
R
1a R = C6H5
1b R = -Pr
i
Figure 1.
2. Results and discussion
The copper-catalyzed condensation of ethyl glyoxylate
with silyl-protected 2-methyl-2-propen-1-ol afforded a-hy-
droxy ester 3 in 71% yield and 83% ee, quite close to the
value obtained by Evans et al.10 (Table 1, entry 2). The
recycling of the catalyst was also possible, with the same
yields (89% and 70% yields) and ee’s (84% and 81%) being
obtained for the 1st and the 2nd recycling, respectively; a
lower yield (35%) was obtained for the 3rd cycle, but the
same enantioselectivity (81% ee) was observed.
The recycling of the catalytic system via the solid/liquid
separation technique was first studied using the condensa-
tion of a-methylstyrene to ethyl glyoxylate under the stan-
dard conditions published in the literature in the case of the
homogeneous system (Eq. 1).
O
Cu(OTf)2/1
CH2Cl2, 25 ºC
+
H
OC2H5
C6H5
CH3
O
We next turned our attention to the recycling of the chiral
catalyst using the FRPSG concept. The FRPSG-supported
catalyst was prepared by mixing the copper triflate and the
fluorous bis(oxazoline) in CH2Cl2, followed by the addition
of the fluorous reverse phase silica gel. Some preliminary
experiments concerning the addition of a-methylstyrene
to ethyl glyoxylate using bis(oxazoline) 1b as the fluorous
ligand in CH2Cl2 at rt gave compound 2 with an ee up to
59% (Table 2, entries 1 and 2); however it was necessary
to use 5 mol % of the catalyst to obtain a moderate chem-
ical yield (51%) after 24 h. Recycling of the catalyst, via a
simple decantation of the solid followed by washes with
CH2Cl2, was effective, with a-hydroxy ester 2 being
obtained in 58% ee for the 2nd run with the same chemical
yield.
ð1Þ
OH
OC2H5
C6H5
O
2
The catalyst was prepared in situ by mixing copper triflate
and fluorous bis(oxazoline) 1a in CH2Cl2. This in situ cat-
alyst effectively promoted the addition of a-methylstyrene
to ethyl glyoxylate at rt, affording a-hydroxy ester 2 in
78% yield and 87% ee (Table 1, entry 1). This enantioselec-
tivity is a little lower than that published by Evans et al.
using the non-fluorous 2,20-isopropylidenebis(4-phenyl-2-
oxazoline) as the chiral ligand, the reaction being, however,
performed in the latest case at 0 ꢁC.10
We performed this condensation under these optimized
conditions using the fluorous bis(oxazoline) 1a as the chiral
ligand. Compound 2 was quantitatively formed after 24 h
in 70% ee (Table 2, entry 3), the value a little lower than that
previously obtained using the homogeneous fluorous
Next, we attempted the recycling of this fluorous copper
catalyst by a simple solid/liquid extraction. After careful
removal of the solvent under reduced pressure, the product
and the unreacted ethyl glyoxylate were extracted several
times with cold hexane, with the catalyst precipitating as
Table 1. Recycling in the glyoxylate-ene reaction using the solid/liquid extraction methodologya
Entry
Olefin
Product
Run
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
34
24
24
24
48
78
76
76
75
78
87 (R)
84 (R)
84 (R)
87 (R)
88 (R)
OH
OC2H5
C6H5
1
C6H5
CH3
O
2
OH
1
2
3
4
48
48
48
48
71
69
70
35
83 (R)
84 (R)
81 (R)
82 (R)
t
-BuPh2SiO
OC2H5
2
t-BuPh2SiO
CH3
O
3
a Reaction conditions: olefin (0.3 mmol), ethyl glyoxylate (3 mmol), Cu(OTf)2 (30 lmol), ligand 1a (30 lmol), CH2Cl2 (5 mL), 25 ꢁC.
b Isolated yields.
c Enantiomeric excess determined by GLC on Cyclodex-b column.

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R. Kolodziuk et al. / Tetrahedron: Asymmetry 18 (2007) 2782–2786
Table 2. Recycling in the glyoxylate-ene reaction using the FRPSG concepta
Entry
1
Olefin
Product
Ligand
Run
—
Time
(h)
Conversionb
(%)
ee (%)
(conf)c
OH
1bd
72
— (38)
59 (R)
OC2H5
OC2H5
C6H5
CH3
C6H5
O
2
OH
C6H5
2
3
1b
1a
1
2
24
24
90 (51)
90 (54)
53 (R)
58 (R)
C6H5
C6H5
CH3
CH3
O
2
OH
1
2
3
4
24
24
24
24
99
99
92
75
70 (R)
61 (R)
60 (R)
51 (R)
OC2H5
C6H5
O
2
OH
4
5
1a
1a
1
2
24
24
90 (61)
90 (64)
81 (R)
82 (R)
t
-BuPh2SiO
OC2H5
t
-BuPh2SiO
CH3
O
3
OH
1
2
3
4
48
48
48
48
90
89
74
70
90 (R)
91 (R)
78 (R)
45 (R)
BnO
OC2H5
BnO
CH3
O
4
O
6
1a
1
2
3
4
5
48
48
48
48
48
50
67
72
70
52
13 (S)
19 (S)
22 (S)
29 (S)
27 (S)
OC2H5
OH
5
a Reaction conditions: olefin (0.3 mmol), ethyl glyoxylate (3 mmol), Cu(OTf)2 (15 lmol), ligand 1a (15 lmol), FSG (3 g), CH2Cl2 (5 mL), 25 ꢁC.
b Conversion determined by GLC, isolated yields in brackets.
c Enantiomeric excess determined by GLC on Cyclodex-b column.
d Cu(OTf)2 (7.5 lmol), ligand 1a (7.5 lmol).
catalyst. The catalytic system could be reused several times;
the conversion could be maintained for two subsequent
runs, with ee of 60% and 61%, respectively, but decreased
to 75% for the 4th run, with 51% ee being, however, ob-
tained in this last run.
decreased for the next two runs (74% and 70% conversion,
78% and 45% ee, respectively).
Finally, the addition of ethyl glyoxylate to methylene
cyclohexane gave the expected a-hydroxy-ester 5 with a
moderate conversion and only 13% ee in favor of the (S)-
enantiomer (Table 2, entry 6). This is in contrast with the
result (79% ee in favor of the (R)-enantiomer) obtained
by Evans et al.10 Several reuses of the catalyst could be per-
formed in this case with no decrease of either the conver-
sion (52–72%) nor of the enantioselectivity (19–29%).
The condensation of ethyl glyoxylate with silyl-protected
2-methyl-2-propen-1-ol afforded a-hydroxy ester 3 in 61%
yield after purification and 81% ee (Table 2, entry 4), very
close to the value obtained previously using the homo-
geneous fluorous complex; the recycling of the catalyst
gave ee up to 82% with 64% chemical yield.
a-Hydroxy ester 4 was obtained by condensation of the
benzyl-protected 2-methyl-2-propen-1-ol with ethyl glyoxy-
late in 90% conversion and 90% ee after 48 h reaction
(Table 2, entry 5), quite close to the value (92% ee) obtained
using the corresponding non-fluorous bis(oxazoline).10 The
catalyst could be reused several times; however, while the
conversion and the enantioselectivity were maintained for
the second run (89% conversion and 91% ee), they
3. Conclusion
In conclusion, we were able to use the fluorous bis(oxazo-
line)/copper complex in the glyoxylate-ene reaction in non-
fluorous solvents, affording the corresponding a-hydroxy
esters in moderate to high ee’s. The catalyst could be easily
isolated and reused several times using the solid/liquid sep-
aration or the FRPSG concept. In the latter case, an unfa-

R. Kolodziuk et al. / Tetrahedron: Asymmetry 18 (2007) 2782–2786
2785
vorable influence of the silica gel on the enantioselectivity
was sometimes observed.
After being stirred for the indicated time at rt, the liquid
phase was removed with a cannular, and the solid was
washed four times with CH2Cl2 (4 · 2 mL). The superna-
tant was removed each time via a syringe after a simple
decantation of the supernatant liquid. The combined
extracts were dried over Na2SO4, and concentrated under
reduced pressure to give an oil that was eventually purified
by column chromatography on silica gel, affording the pure
adduct. The enantiomeric excess of the pure product or of
the raw oil was determined by GLC on Cyclodex-b col-
umn. The immobilized catalyst was reused in the next cat-
alytic ene-reaction without further addition of copper
triflate or ligand 1.
4. Experimental
4.1. General
Solvents were purified by standard methods and dried if
necessary. All commercially available reagents were used
as received. tert-Butyldiphenyl(prop-1-en-2-yloxy)silane,11
1-[(2-methylallyloxy)methyl]benzene,12 and the fluorous
bis(oxazolines) 1a–b6c were prepared according to litera-
ture procedure. FluoroFlashꢂ Silica Gel, 40 lm, was
obtained from Fluorous technologies, Inc. Reactions
involving organometallic catalysis were carried out in a
Schlenk tube under an inert atmosphere. The NMR spectra
(1H: 300 MHz, 13C: 75.4 MHz) were recorded on a Bruker
AC 300 instrument with Me4Si and CDCl3 as the internal
standard, respectively. Ee’s of compounds 2–5 were deter-
mined by GLC on Cyclodex-b column. The absolute con-
figuration of the enantiomers was determined by
comparison of the retention times with those of authentic
samples.
Acknowledgment
´
One of us (R.K.) thanks the Region Rhone-Alpes for a
post-doctoral fellowship.
References
1. (a) Transitions Metals for Organic Synthesis, 2nd ed.; Beller,
M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004; (b)
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 2003; Vols. 1–3; (c)
Asymmetric Catalysis on Industrial Scale; Blaser, H. U.,
Schmidt, E., Eds.; Wiley-VCH: Weinheim, 2004.
4.2. General procedure for the recycling using the solid/liquid
extraction methodology
The catalyst was prepared in situ in a Schlenk tube under
nitrogen by mixing Cu(OTf)2 (10.9 mg, 30 lmol), and
ligand 1a (37 mg, 30 lmol) in dichloromethane (2.5 mL) at
rt for 3 h. To this solution, the olefin (0.3 mmol) and ethyl
glyoxylate (306 mg, 3 mmol, 50% solution in toluene) were
added. After being stirred for the indicated time at rt, the
solvent was almost removed under reduced pressure, and
the residue was successively diluted four times with cold
hexane (4 · 2 mL), giving a blue-green precipitate. The
supernatant was removed each time via a syringe after sim-
ple decantation of the supernatant liquid. The combined
organic layers were dried over Na2SO4, and concentrated
under reduced pressure to give an oil that was purified by
column chromatography on silica gel, affording the pure
adduct, whose enantiomeric excess was determined by
GLC on Cyclodex-b column. The recovered catalyst was
used in the next catalytic ene-reaction without further addi-
tion of copper triflate or ligand 1a.
2. (a)Multiphase Homogeneous Catalysis; Cornils, B., Herr-
´
mann, W. A., Horvath, I. T., Leitner, W., Mecking, S.,
Olivier-Bourbigou, H., Vogts, D., Eds.; Wiley-VCH: Wein-
heim, 2005; (b) Catalyst Separation, Recovery and Recycling;
Cole-Hamilton, D. J., Tooze, R. P., Eds.; Springer: Berlin,
2006.
3. (a) Sinou, D. In Handbook of Fluorous Chemistry; Gladysz, J.
´
A., Curran, D. P., Horvath, I. T., Eds.; Wiley-VCH:
Weinheim, 2004; pp 306–315; (b) Biffis, A.; Braga, M.;
Cadamuro, S.; Tubaro, C.; Basato, M. Org. Lett. 2005, 7,
1841–1844; (c) Bayardon, J.; Sinou, D. Tetrahedron: Asym-
metry 2005, 16, 2965–2972; (d) Bayardon, J.; Sinou, D.;
Holczknecht, O.; Mercs, L.; Pozzi, G. Tetrahedron: Asym-
metry 2005, 16, 2319–2327.
4. (a) Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837–
11865; (b) Croxrall, B.; Hope, E. G.; Stuart, A. M. Chem.
Commun. 2003, 2430–2431; (c) Curran, D. P.; Fisher, K.;
Moura-Letts, G. Synlett 2004, 1379–1382; (d) Matsugi, M.;
Curran, D. P. J. Org. Chem. 2005, 70, 1636–1642; (e)
Cavazzini, M.; Quici, S.; Pozzi, G. Tetrahedron 2002, 58,
3943–3949.
4.3. General procedure for the recycling using the FRPSG
concept
5. Hope, E. G.; Stuart, A. M.; West, A. J. Green Chem. 2004, 6,
345–350.
The copper catalyst was prepared in situ in a Schlenk tube
under a nitrogen by mixing Cu(OTf)2 (5.5 mg, 15 lmol),
and ligand 1 (15 lmol) in dichloromethane (2.5 mL) at rt
for 3 h. This solution containing the in situ formed catalyst
was added to a Schlenk tube containing the fluorous re-
verse phase silica gel (3 g) in BTF (5 mL). The mixture
was stirred at rt for 1 h, after which the solvents were evap-
orated under reduced pressure, and the solid obtained was
dried in vacuo to give the FRPSG-supported copper com-
plex. The olefin (0.3 mmol) and ethyl glyoxylate (306 mg,
3 mmol, 50% solution in toluene) dissolved in dichloro-
methane (5 mL), were added to this supported complex.
6. (a) Mino, T.; Sato, Y.; Saito, A.; Tanaka, Y.; Satome, H.;
Sakamoto, M.; Fujita, T. J. Org. Chem. 2005, 70, 7979–7984;
(b) Bayardon, J.; Holczknecht, O.; Pozzi, G.; Sinou, D.
Tetrahedron: Asymmetry 2006, 17, 1568–1572; (c) Bayardon,
J.; Sinou, D. J. Org. Chem. 2004, 69, 3121–3128.
7. (a) Horn, J.; Michalek, F.; Tzschucke, C. C.; Bannwarth, W.
Top. Curr. Chem. 2004, 242, 43–75; (b) Schneider, S.;
Bannwarth, W. Angew. Chem., Int. Ed. 2000, 39, 4142–
4145; (c) Tzchucke, C. C.; Markert, C.; Glatz, H.; Bann-
warth, W. Angew. Chem., Int. Ed. 2002, 41, 4500–4503; (d)
Tzschucke, C. C.; Bannwarth, W. Helv. Chim. Acta 2004, 87,
2882–2889; (e) Biffis, A.; Braga, M.; Basato, M. Adv. Synth.
´
Catal. 2004, 346, 451–458; (f) Garcia-Bernabe, A.; Tzschucke,

2786
R. Kolodziuk et al. / Tetrahedron: Asymmetry 18 (2007) 2782–2786
C. C.; Barnnwarth, W.; Haag, R. Adv. Synth. Catal. 2005, B.; Orlandi, S.; Benaglia, M.; Pozzi, G. Eur. J. Org. Chem.
347, 1389–1394; (g) Hope, E. G.; Sherrington, J.; Stuart, A.
M. Adv. Synth. Catal. 2006, 348, 1635–1639; (h) Tzschucke,
C. C.; Andrushko, V.; Bannwarth, W. Eur. J. Org. Chem.
2005, 5248–5261; (i) Michalek, F.; Bannwarth, W. Helv.
Chim. Acta 2006, 89, 1030–1067.
2004, 2669–2673.
10. (a) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.;
Tregay, S. W. J. Am. Chem. Soc. 1998, 120, 5824–5825; (b)
Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.;
Vojkovsky, T. J. Am. Chem. Soc. 2000, 122, 7936–7943.
11. Waser, J.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc.
2005, 127, 8294–8295.
8. Horn, J.; Bannwarth, W. Eur. J. Org. Chem. 2007, 2058–
2063.
9. (a) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.;
Pozzi, G. Eur. J. Org. Chem. 2003, 1191–1197; (b) Simonelli,
12. Steinreiber, A.; Hellstrom, H.; Mayer, S. F.; Orru, R. V. A.;
Faber, K. Synlett 2001, 111–113.