New perfluoroalkyl-substituted bisoxazolines as chiral ligands in asymmetric CuII-catalyzed reactions

Article abstract of DOI:10.1002/ejoc.200400035

Two new enantiomerically pure perfluoroalkyl-substituted bisoxazolines (F-Box) have been prepared by a reaction sequence that involves formation of the properly functionalized Box followed by introduction of one or two H-C ₈F₁₇ resid

Full text of DOI:10.1002/ejoc.200400035

FULL PAPER
New Perfluoroalkyl-Substituted Bisoxazolines as Chiral Ligands in Asymmetric
CuII-Catalyzed Reactions
Barbara Simonelli,[a] Simonetta Orlandi,[a] Maurizio Benaglia,*[a] and Gianluca Pozzi[b]
Keywords: Biphasic catalysis / Chiral bisoxazolines / Fluorous ligands / Fluorous silica gel chromatography /
Homogeneous catalysis
Two new enantiomerically pure perfluoroalkyl-substituted
bisoxazolines (F-Box) have been prepared by a reaction se-
quence that involves formation of the properly functionalized
Box followed by introduction of one or two n-C8F17 residues.
fluorous bisoxazolines that we have reported previously. In
both cases, the F-Box that has the lower fluorine content per-
formed better, in terms of chemical yield and enantioselectiv-
ity, than the more-fluorinated one. The recovery and recyc-
These ligands were employed for the first time in the Mukai- ling of the ligands is realized either by phase separation of
yama aldol addition of silylketene thioacetals to methylpy-
ruvate promoted by Cu(OTf)2 (up to 85% ee) and in the ene
reaction between α-methylstyrene and ethylglyoxalate in the
presence of Cu(OTf)2 (up to 74% ee). We compared the react-
ivities of the new ligands with those of two other chiral
the reaction solvents or by filtration through a short plug of
fluorous silica gel.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
reactions, and Sinou’s group reported[7] the use of perfluori-
nated bis(oxazolines) in palladium-promoted allylic alky-
lations. Here we report the synthesis of two new enantiom-
erically pure perfluoroalkyl-substituted bisoxazolines (F-
Box) and their use in asymmetric Mukaiyama aldol and
ene-type reactions.
The use of perfluorous solvents for liquidϪliquid separ-
ation technologies is receiving a rapidly growing amount
of attention.[1] Fluorous biphasic reactions are based upon
interactions between fluorous solvents and fluorous com-
pounds, such as catalysts, reagents, and substrates; at the
end of the reaction, non-fluorinated products are usually
extracted from a fluorous phase into an organic phase,
while fluorinated compounds are recovered from the
fluorous phase.[2] Although fluorous biphasic catalysis rep-
resents an environmentally attractive alternative to tra-
ditional catalytic methods, relatively few chiral fluorous li-
gands have been studied so far.[3] Such ligands include
salen-based derivatives that form cobalt and manganese
complexes,[3a,3b] BINOL compounds that act as titanium
ligands,[3c,3d] and iridium complexes of diimines and diam-
ines,[3e] BINAP and MOP derivatives.[3a,3f,3g] Surprisingly,
despite the recognized versatility of bis(oxazoline) (Box) li-
gands in asymmetric synthesis,[4] only two reports so far
have dealt with the synthesis and application of perfluori-
nated bis(oxazolines).[5] In particular, we realized[6] the syn-
thesis of chiral fluorous bis(oxazolines), which we employed
in CuI-promoted cyclopropanation and CuII-catalyzed ene
Results and Discussion
The synthesis of the new chiral fluorous bis(oxazolines),
designed on the basis of our previous work with PEG-sup-
ported Box,[8] is illustrated in Scheme 1. The tert-butyl-sub-
stituted, commercially available Box 1 was converted in two
steps (70% overall yield) into the bis(phenol) 2,[8] which was
reacted with 3-perfluorooctyl-1-iodopropane 3,[9] in pres-
ence of cesium carbonate, to give ligand 4 in 56% yield.
Analogously, bis(oxazoline) 5,[6] prepared in 30% overall
yield, was transformed into the perfluoroalkyl-substituted
Box 6 (48% yield).
The fluorine contents of the new F-Box ligands 4 and 6
were calculated to be 46.2 and 38.1%, respectively. As ex-
pected on the basis of the relatively low fluorine content,
both of these new F-bis(oxazolines) are readily soluble in
non-fluorinated solvents and may be classified as light
fluorous substances.[10] It is worth mentioning that the pre-
viously synthesized F-Box ligands 7 and 8[8] (Figure 1) had
fluorine contents of 49.2 and 55.5%, respectively. While the
former is soluble in organic solvents, 8 has a partition coef-
ficient of 4.7 in n-perfluorooctane/dichloromethane (50:50,
v/v) and of 17.5 in n-perfluorooctane/acetonitrile (50:50, v/v).
[a]
Centro di Eccellenza CISI, and Dipartimento di Chimica
Organica e Industriale,
Universita’ degli Studi di Milano
Via Golgi 19, 20133 Milano, Italy
Fax: (internat.) ϩ 39-02-5031-4159
E-mail: maurizio.benaglia@unimi.it
[b]
CNR-ISTM, Universita’ degli Studi di Milano
Via Golgi 19, 20133 Milano, Italy
Eur. J. Org. Chem. 2004, 2669Ϫ2673
DOI: 10.1002/ejoc.200400035
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B. Simonelli, S. Orlandi, M. Benaglia, G. Pozzi
FULL PAPER
Scheme 2. Enantioselective ene reactions catalyzed by the metal
complexes of F-box ligands 4 and 6؊8
Thus the reactivity of the new ligand 6 compares favor-
ably with that of ligand 7 (67% ee), and 8 (26% ee in a 1:1
CH2Cl2/perfluorooctanes mixture; see entries 3Ϫ4 in
Table 1).[6]
Next we studied the enantioselective addition of enolsil-
ane to pyruvate esters.[12] We employed the CuII complexes
of fluorous bis-oxazolines, generated by stirring the ligand
and Cu(OTf)2 in dry dichloromethane for 3 h at 25 °C, to
promote the reaction between methyl pyruvate 11 and silyl-
ketene acetal 12. Typically, methyl pyruvate (0.5 mmol) and
silylketene acetal (0.6 mmol) were added to a solution of
the catalyst (0.05 mmol, 10 mol%) in the appropriate sol-
vent (2 mL) at 0 °C. The resulting mixture was stirred over-
night while the temperature slowly increased from 0 °C to
room temp.
Scheme 1. Synthesis of F-box ligands 4 and 6
By employing the F-Box 7 in dry CH2Cl2, we obtained
the product 13 in 55% yield and 83% ee (Table 1, entry 5).
Running the reaction in THF resulted in a slight increase
in the yield (from 55 to 63%), but also to a decrease in
the enantiomeric excess (from 83 to 65%; Table 1, entry 6).
Surprisingly, the reaction employing the C2-symmetric F-
Box 4 in dichloromethane and 8 in a 1:1 CH2Cl2/perfluoro-
octanes mixture afforded the product in very low yields and
with practically no enantioselectivity (Table 1, entries 7 and
8). Finally, the use of ligand 6 in dry dichloromethane led
to the hydroxy ester 13 being obtained in 65% yield and
85% ee (Table 1, entry 9). It is worth mentioning that under
the same reaction conditions, Evans’ bis-oxazoline 14 (see
Figure 1) promoted the Mukaiyama aldol reaction in 71%
yield and 92% ee.[13]
The data collected in Table 1 indicate that the C1-sym-
metric ligands 6 and 7 performed constantly better than the
C2-symmetric ligands 4 and 8 in terms of enantioselectivity.
In the best case for the ene reaction, we observed the ee to
Figure 1. Structures of F-box ligands 4, 6؊8, and 14
The copper() complexes of these four chiral F-Box li- be ca. 15% lower than those obtained with the best ligands
gands, which have different fluorine contents and solubility reported in the literature.[11,14] Indeed, the use of F-Box 6
properties, were tested in two important enantioselective in the ene reaction led to product 10 in 74% ee; Evans ob-
CϪC bond-forming processes: the ene reaction and the tained an 89% ee by using the catalyst derived from Box 14.
Mukaiyama aldol addition.
In the aldol reaction, the use of ligands 4 and 8 afforded
The ene reaction[11] (Scheme 2) between α-methylstyrene an essentially racemic product in low chemical yields; once
9 (1 mol equiv.) and ethyl glyoxalate (50% solution in tolu- again, 6 and 7 clearly performed better (83 and 85% ee). It
ene, 10 mol equiv.), which we performed from 0 °C to room is noteworthy that the enantiomeric excess obtained using
temp. over 18 h in CH2Cl2 in the presence of ligand 6 (11 F-Box 6 (85% ee) is only slightly inferior to that obtained
mol%) and Cu(OTf)2 (10 mol%), afforded adduct 10 in 65% using Box 14 (92% ee).
yield and 74% ee, as determined by the Mosher ester
These findings seem to suggest some negative effects ex-
method (Table 1, entry 1). When the reaction was repeated erted by the perfluorinated ‘‘ponytails’’.[15] An explanation
under the same conditions, but using ligand 4, the product of these effects is not easy to provide, however, because
was obtained in 73% chemical yield, but only 7% ee there is no clear inverse relationship between the fluorine
(Table 1, entry 2).
loading of the ligands and the enantioselectivity observed in
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Chiral Ligands in Asymmetric CuII-Catalyzed Reactions
FULL PAPER
Table 1. Enantioselective reactions catalyzed by F-box ligands 4 and 6؊8 in dry dichloromethane.
Entry
Equation
Catalyst (10 mol %)
Product
Isolated yield%
ee %[a]
Recov. yield %
1
2
1
1
1
1
2
2
2
2
2
2
1
6/Cu(OTf)2
4/Cu(OTf)2
7/Cu(OTf)2
8/Cu(OTf)2
7/Cu(OTf)2
7/Cu(OTf)2
4/Cu(OTf)2
8/Cu(OTf)2
6/Cu(OTf)2
6/Cu(OTf)2
6/Cu(OTf)2
10
10
10
10
13
13
13
13
13
13
10
65
73
99
64
55
63
15
10
65
63
62
74
7
67
26
83
65
7
78[b]
80[b]
77[b]
89[d]
80[b]
77[b]
84[b]
85[d]
85[b]
74[b]
72[b]
3
4[c]
5
6[e]
7
8[c]
9
4
85
82
71
10[f]
11[g]
[a]
Determined by the Mosher ester method (in the case of compound 10) or by HPLC on a chiral stationary phase (in the case of
[b]
[c]
compound 13).
Ligand recovered by fluorous-phase silica gel chromatography.
Reaction run in a 1:1 CH2Cl2/perfluorooctanes
mixture. [d] Ligand recovered by phase separation. [e] Reaction run in dry tetrahydrofuran. [f] Reaction performed using a sample of ligand
[g]
6 recycled from the reaction of entry 9 (see text). Reaction performed using a sample of ligand 6 recycled from the reaction of entry
1 (see text).
moter of the aldol condensation, its recovery was ac-
complished successfully in 85% yield, which is similar to its
89% recovered yield after the ene reaction.[6]
The low fluorine content of the other F-Box does not
allow us to use the same procedure. It has already been
Scheme 3. Enantioselective aldol reactions catalyzed by the metal
demonstrated that 7 can be recovered chromatographically
complexes of F-box ligands 4 and 6؊8
using a short silica gel column.[6] In the present work,
fluorous solid-phase extraction (FSPE) made the recovery
of the ligands even easier.[20] Indeed, in the Mukaiyama al-
their reactions. It is possible that the two highly fluorinated
dol reaction, the ligands 4, 6, and 7 were isolated in 84, 85,
and 80% yields, respectively, by simple filtration through a
very short plug of fluorous reverse-phase silica gel (see Exp.
Sect.).[21] The F-Box ligands we recovered from both the
ene and aldol reactions were pure compounds to within the
detection limits of 1H and 19F NMR spectroscopic analysis.
We reused the recovered ligands in new reactions; for ex-
ample, recycling of 6 in the aldol condensation (Table 1,
entry 10) afforded product 13 in 63% yield and 82% ee;
these values are very similar to those obtained when we
used a fresh sample of ligand (entry 9). The ligand reco-
vered in the ene reaction was also recycled with good results
(entry 11): the product 10 was isolated in 62% yield and
71% ee; these values are similar to those obtained when
using the fresh ligand (65% yield, 74% ee; Table 1, entry 1).
substituents positioned at the bridging carbon atom in the
F-Box ligands may experience strong steric repulsions that
reduce the ‘‘bite angles’’ of the Box moieties and lead to
the ligands having greater difficulty in complexing with cop-
per ions; this situation, consequently, leads to poorly en-
antioselective transformations.[16] This negative effect
should be especially evident in reactions catalyzed by Box/
CuII complexes that adopt a square-planar geometry; these
reactions are known to be particularly sensitive to the Box
‘‘bite angle’’.[17] Indeed, the bridging substitution in the C1-
symmetric ligands 6 and 7 is less sterically demanding than
it is in 4 and 8, and the ligandϪcopper cation complexation
should be similar to that of the commercially available Box
14. The very different behavior of ligands that have similar
fluorine content, such as 7 (49.2%) and 4 (46.2%), suggests
that the spatial arrangement of the fluorous ‘‘ponytails’’
plays a major role in determining the efficiency of the chi-
ral ligands.[18]
Conclusions
Next, we studied the recovery of the fluorous bis-oxazol-
ines. First, the ligands were released from the copper cation
In conclusion, the synthesis of two new perfluorinated
in the crude reaction mixture by decomplexation with an bisoxazoline (F-Box) ligands having different fluorine con-
aqueous solution containing cyanide ions.[19] After stand- tents and solubility properties is described. We employed
ard workups of both the Mukaiyama aldol and ene reac- the CuII triflate complexes of these compounds in two cata-
tions, we recovered ligand 8 by separation of the CH2Cl2/ lytic enantioselective transformations to afford the products
perfluorooctanes mixture and evaporation of the latter sol- in good chemical yields; the enantiomeric excesses are only
vent. The ligands recovered from both reactions were stable slightly inferior to those reported in the literature.[11,12]
under the reaction and recovery conditions, as evidenced by
Recovery of the F-Box is possible by either of two pro-
1
their H and 19F NMR spectra being identical to those of cedures: phase separation in one case and a very easy fil-
fresh samples. Although ligand 8 was not an efficient pro- tration through a short plug of fluorous silica gel in the
Eur. J. Org. Chem. 2004, 2669Ϫ2673
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B. Simonelli, S. Orlandi, M. Benaglia, G. Pozzi
FULL PAPER
cooled mixture was poured into water (5 mL) and extracted with
Et2O (4 ϫ 10 mL). The combined organic phases were washed with
water (5 mL), dried over Na2SO4, and concentrated under vacuum.
The residue was purified by flash chromatography (hexanes/Et2O,
9:1) to give the product (0.046 g, 0.054 mmol, 48% yield) as a thick
pale-yellow oil. [α]2D2 ϭ Ϫ44.7 (c ϭ 0.58 in CHCl3). IR: ν˜ ϭ 3054,
other. The recovered ligands can be recycled to afford reac-
tion products in chemical yields and enantioselectivities
that are almost identical to those obtained in the first cycle.
Experimental Section
1
2981, 1673 cmϪ1. H NMR: δ ϭ 0.86 (s, 18 H, tBu), 1.4 (s, 3 H),
2
2.0Ϫ2.4 (m, 4 H), 3.11 (A part of AB system, JH,H ϭ 14.2 Hz, 2
General: 1H NMR spectra were recorded at 300 MHz in CDCl3
unless otherwise stated, and were referenced to tetramethylsilane
(TMS) at δ ϭ 0.00 ppm. 13C NMR spectra were recorded at
75 MHz and were referenced to CDCl3 at δ ϭ 77.0 ppm. 19F NMR
spectra were recorded at 282 MHz in CDCl3 and were referenced
to hexafluorobenzene at δ ϭ 0.0 ppm. Optical rotations were meas-
ured at the Na-D line in a 1-dm cell at 22 °C. IR spectra were
recorded using thin films or solutions in CH2Cl2.
Adducts 10 and 13 are known compounds having established abso-
lute configurations.[11,12] The ee of compound 10 was determined
by analyzing the 1H NMR spectra of the corresponding Mosher
ester obtained by reaction with the (R)-enantiomer of the Mosher
acid chloride. The esters gave signals identical to those reported by
Evans (see the Supporting Information of ref.[11]). The diagnostic
signals were those of the vinyl protons that resonate at δ ϭ 5.40
and 5.22 ppm for the major (R,R)-isomer and at δ ϭ 5.23 and
5.02 ppm for the minor (S,R)-isomer. The ee of compound 13 was
determined by performing HPLC on a chiral stationary phase: Chi-
racel OD column; eluent, hexane/ iPrOH (99:1); flow rate, 1 mL/
min; λ ϭ 210 nm. Minor enantiomer: TR ϭ 7.64 min; major enanti-
omer: TR ϭ 8.39 min.
2
H, one proton of ArCH2), 3.39 (B part of an AB system, JH,H
ϭ
14.2 Hz, 2 H, one proton of ArCH2), 3.7Ϫ4.2 (m, 8 H, two protons
of oxazoline CH2 and two protons of ArOCH2), 6.75 (A part of
3
an AB system, JH,H ϭ 8.6 Hz, 4 H, aromatic protons ortho to O),
3
7.05 (B part of an AB system, JH,H ϭ 8.6 Hz, 4 H, aromatic pro-
2
tons meta to O) ppm. 13C NMR: δ ϭ 20.6, 25.8, 28 (t, JC,F
ϭ
22.0 Hz), 33.9, 38.6, 48.7, 66.3, 68.3, 75.6, 113.9, 120.5Ϫ105.5 (m,
C8F17), 129.6, 131.6, 157.3, 162.2, 166.2 ppm. 19F NMR: δ ϭ
Ϫ126.3, Ϫ122.2, Ϫ121.8, 118.5, 113Ϫ106, 81.3 ppm.
C34H39F17N2O3 (846.66): calcd. C 48.23, H 4.64, N 3.31; found C
48.14, H 4.59 N, 3.27.
Stereoselective Syntheses Promoted by Chiral F-Box Ligands
Ene Reaction: A solution was prepared by dissolving the chiral li-
gand (0.030 mmol) and Cu(OTf)2 (0.012 g, 0.033 mmol) under ni-
trogen in dry CH2Cl2 (2 mL). The resulting dark-green solution
was stirred at room temp. for 4 h and then it was added to a mix-
ture of α-methylstyrene (0.039 mL, 0.3 mmol) and ethylglyoxalate
(0.595 mL of a 50% solution in toluene, 3.0 mmol) that had been
cooled to 0 °C. The resulting mixture was stirred overnight while
the temperature slowly increased to room temp. The mixture was
then concentrated under vacuum; the residue was dissolved in
CH2Cl2 (5 mL), dried over Na2SO4, filtered, and concentrated un-
der vacuum to give a crude product that was purified by flash chro-
matography (hexanes/Et2O, 7:3). Yields and values of ee of the
product are reported in Table 1.
2,2-Bis{2-[(4S)-(1,1-dimethylethyl)-1,3-oxazolinyl]}-1,3-bis{4-[3-
(perfluorooctyl)propoxy]phenyl}propane:
Cesium
carbonate
(0.344 g, 1.057 mmol) and 3-perfluorooctyl-1-iodopropane[16]
(0.160 g, 0.272 mmol) were added to a solution of 2,2-bis{2-[(4S)-
(1,1-dimethylethyl)-1,3-oxazolinyl]}-1,3-bis(4-hydroxyphenyl)pro-
pane[6] (0.072 g, 0.151 mmol) in DMF (2 mL) that was stirred un-
der nitrogen at 50 °C. The mixture was then stirred at 50 °C for a
further 60 h. The cooled mixture was poured into water (5 mL) and
extracted with Et2O (4 ϫ 10 mL). The combined organic phases
were washed with water (5 mL), dried over Na2SO4, and concen-
trated under vacuum. The residue was purified by flash chromatog-
raphy (hexanes/ Et2O, 8:2) to give the product (0.106 g,
0.076 mmol, 56% yield). M.p. Ͼ 150 °C dec. [α]2D2 ϭ Ϫ19.5 (c ϭ
0.8 in CHCl3). IR: ν˜ ϭ 3051, 2955, 1656 cmϪ1. 1H NMR: δ ϭ 0.86
(s, 18 H, tBu), 2.10 (m, 4 H, ArOCH2CH2), 2.33 (m, 4 H,
C8F17CH2), 3.11 (A part of AB system, 2JH,H ϭ 14.2 Hz, 2 H, one
Mukaiyama Aldol Reaction: A solution was prepared by dissolving
the chiral ligand (0.030 mmol) and Cu(OTf)2 (0.012 g, 0.033 mmol)
in dry CH2Cl2 (2 mL) under nitrogen. The resulting dark-green
solution was stirred at room temp. for 3 h, cooled to 0 °C, and
added to a mixture of methyl piruvate (0.035 g, 0.30 mmol) and
trimethylsilyl tert-butylthioketene acetal (0.082 g, 0.40 mmol) in
dry CH2Cl2 (2 mL) that had been cooled to 0 °C. After stirring at
that temperature for 1 h, the temperature of the stirring reaction
mixture was increased slowly to room temp. The mixture was then
filtered through a short plug of silica gel and concentrated under
vacuum to give a crude product that was analyzed by GC. The
crude silyl ether was then hydrolyzed with 1  HCl in THF to yield
the hydroxy ester, which was purified by flash chromatography The
values of ee were determined by HPLC analysis on a Chiracel OD
column (hexane/2-propanol, 99:1; flow rate: 1 mL/min; minor en-
antiomer: TR ϭ 7.64 min; major enantiomer: TR ϭ 8.39 min).
In the ligand recovery procedure, the crude reaction mixture dis-
solved in CH2Cl2 was treated with a aqueous solution of KCN;
the organic phase was separated, dried over Na2SO4, filtered, and
concentrated under vacuum to give the crude product, which was
loaded onto a short plug of fluorous reverse-phase silica gel (diam-
eter: 0.7 cm, length: 5Ϫ7 cm). The product was recovered upon
eluting with CH3CN (10Ϫ15 mL); in a few cases, the product was
contaminated by traces of the fluorous ligand). The chiral F-Box
2
proton of ArCH2), 3.39 (B part of AB system, JH,H ϭ 14.2 Hz, 2
3
H, one proton of ArCH2), 3.83 (dd, JH,H ϭ 7.6, 10.1 Hz, 2 H,
CHBu-t), 3.98Ϫ4.10 (m, 8 H, two protons of oxazoline CH2 and
3
two protons of ArOCH2), 6.79 (A part of AB system, JH,H
ϭ
8.6 Hz, 4 H, aromatic protons ortho to O), 7.19 (B part of AB
3
system, JH,H ϭ 8.6 Hz, 4 H, aromatic protons meta to O) ppm.
2
13C NMR: δ ϭ 21.6, 26.5 (t, JC,F ϭ 20.0 Hz), 33.6, 33.9, 41.2,
43.5, 68.5, 74.5, 75.5, 114.4, 119.5Ϫ106.5 (m, C8F17), 129.3, 130.2
2
(t, JC,F ϭ 22.5 Hz), 156.9, 167.7 ppm. 19F NMR: δ ϭ Ϫ126.6,
Ϫ123.2, Ϫ122, 118, 115Ϫ106, 81.3 ppm. C51H48F34N2O3 (1382.51):
calcd. C 43.79, H 3.46, N 2.00; found C 43.70, H 3.39, N 2.02.
2,2-Bis{2-[(4S)-(1,1-dimethylethyl)-1,3-oxazolinyl]}-1-{[4-(3-
perfluorooctyl)propoxy]phenyl]propane: Cesium carbonate (0.130 g,
0.400 mmol) and 3-perfluorooctyl-1-iodopropane[16] (0.067 g,
0.114 mmol) were added to a solution of 2,2-bis{2-[(4S)-(1,1-di-
methylethyl)-1,3-oxazolinyl]}-1-(4-hydroxyphenyl)propane[6] (0.044 g, was then recovered by eluting with CH2Cl2 (15 mL). The recovered
0.114 mmol) in DMF (2 mL) that was stirred under nitrogen at 50
°C. The mixture was stirred at 50 °C for an additional 60 h. The
chiral ligands exhibited NMR spectra identical to those of the
freshly synthesized samples.
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Chiral Ligands in Asymmetric CuII-Catalyzed Reactions
FULL PAPER
[10]
[11]
J. A. Gladysz, D. P. Curran, Tetrahedron 2002, 58, 3823Ϫ3825.
D. A. Evans, S. W. Tregay, C. S. Burgey, N. A. Paras, V. I.
Vojkovsky, J. Am. Chem. Soc. 2000, 122, 7936Ϫ7943.
D. A. Evans, M. C. Kozlowski, C. S. Burgey, D. W. C. MacMil-
lan, J. Am. Chem. Soc. 1997, 119, 7893Ϫ7894.
The enantiomeric excess of the product obtained when we em-
ployed Box 14 (91% ee) is similar to that reported in the litera-
ture (92% ee at 20 °C); see ref.[12]
Acknowledgments
This work was supported by MIUR (Progetto Nazionale Stereose-
lezione in Sintesi Organica; Metodologie ed Applicazioni),
C.I.N.M.P.I.S. (Consorzio Interuniversitario Nazionale Metodolo-
gie e Processi Innovativi di Sintesi), and CNR-ISTM.
[12]
[13]
[1]
[1a]
[14]
Some reviews on fluourous biphase chemistry:
I. T. Horv-
When the Cu(OTf)2 complexes of ligands 4 and 6 were em-
ployed to catalyze the DielsϪAlder cycloaddition between
cyclopentadiene and N-acryloyloxazolidinone, the correspond-
ing cycloadducts were obtained with low ee; the chemical yield
when using 6 was good, but it was very poor when using 4.
We note that this behavior is not a general feature of chiral
fluorinated catalysts because in other cases they perform as
efficiently as their non-fluorinated counterparts. See ref.[3]
For a recent discussion on the influence that the substitution
pattern at the Box bridging carbon atom has on the steric co-
urse of Box-mediated asymmetric syntheses see: S. E.
Denmark, C. M. Stiff, J. Org. Chem. 2000, 65, 5875Ϫ5878, and
references cited therein.
J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325Ϫ335.
For examples of the influence that even small changes to the
Box ‘‘bite angle’’ have on the enantioselectivity of chiral Box/
CuII-promoted reactions, see: I. W. Davies, R. J. Deeth, R. D.
Larsen, P. J. Reider, Tetrahedron Lett. 1999, 40, 1233Ϫ1236.
See ref.[3] For a discussion on the insulating effects of structur-
ally different spacers in perfluorinated ligands, see: I. T. Horv-
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Received January 19, 2004
Eur. J. Org. Chem. 2004, 2669Ϫ2673
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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