Synthesis of two new chiral fluorous bis(oxazolines) and their applications as ligands in catalytic asymmetric reactions

Article abstract of DOI:10.1016/j.tetasy.2005.08.013

Two new chiral fluorous bis(oxazolines) with a fluorous content of 56.9% and 59.3%, respectively, have been prepared starting from (S)-serine and (S)-tyrosine. Applications of these compounds as fluorous box ligands in asymmetric alkylations gave ees up to 92%, and in allylic oxidations ees up to 50%. Recycling and reuse of the ligands in asymmetric alkylation and of the catalytic system in allylic oxidation gave the same enantioselectivities.

Full text of DOI:10.1016/j.tetasy.2005.08.013

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2965–2972
Synthesis of two new chiral fluorous bis(oxazolines) and
their applications as ligands in catalytic asymmetric reactions
Jerome Bayardon and Denis Sinou*
`
´
Laboratoire de Synthese Asymetrique, associe au CNRS, ESCPE Lyon, Universite Claude Bernard Lyon 1, 43,
boulevard du 11 novembre 1918, 69622 Villeurbanne Cedex, France
´
´
Received 19 July 2005; accepted 8 August 2005
Abstract—Two new chiral fluorous bis(oxazolines) with a fluorous content of 56.9% and 59.3%, respectively, have been prepared
starting from (S)-serine and (S)-tyrosine. Applications of these compounds as fluorous box ligands in asymmetric alkylations gave
ees up to 92%, and in allylic oxidations ees up to 50%. Recycling and reuse of the ligands in asymmetric alkylation and of the catal-
ytic system in allylic oxidation gave the same enantioselectivities.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ties have been obtained, and the chiral catalysts, or at
least the chiral ligands, were easily recovered and reused
with the same enantioselectivities.
The C2-symmetric enantiopure bis(oxazolines) (box)
have emerged as one of the most efficient classes of
chiral ligands in the field of asymmetric organometallic
catalysis.1–7 The broad range of applications of these
chiral ligands and the very high enantioselectivities
obtained have stimulated an intense research activity
concerning their immobilization on supports in order
to recover and recycle the chiral catalyst.8 This hetero-
genization has been performed using bonding to solid
inorganic9–15 or organic supports,16,17 as well as to solu-
ble organic polymers.18–21 These different approaches
gave enantioselectivities quite similar to those obtained
using usual homogeneous conditions.
Herein, we report the synthesis of two new fluorous
bis(oxazolines) having a fluorine content as high as
59% and their use as chiral ligands in three representa-
tive enantioselective catalytic reactions.
2. Results and discussion
In our paper concerning the use of chiral fluorous
bis(oxazolines) in allylic alkylation and allylic oxidation,
although enantioselectivities as high as those obtained
using non-fluorous bi(oxazolines) were obtained, the
main problem was the recycling of the catalyst. In order
to try to circumvent this problem, one solution was to
increase the fluorine content of the bis(oxazoline), by
the introduction of more than two fluorous ponytails.
The fluorous biphase catalysis is quite a new concept.22
In this approach, a soluble and easily recoverable ligand
can be obtained by the introduction of fluorous pony-
tails in the molecule. This approach has been extended
more or less successfully to some asymmetric organo-
metallic catalysis in a two-phase system organic sol-
vent–fluorous solvent. Some perfluoroalkyl-substituted
chiral box ligands have been reported by us23,24 and
by Benaglia and co-workers,25 and used as ligands in
allylic alkylation, allylic oxidation, cyclopropanation,
and ene reactions. In most cases, high enantioselectivi-
Treatment of (S)-serine with di-tert-butyl dicarbonate
(Boc2O) in dioxane in the presence of sodium hydroxide
gave quantitatively (S)-N-Boc-serine 3.26 Amino acid 3
was reacted with sodium hydride (2.2 mol equiv) in
DMF at room temperature, and then alkylated first with
allyl bromide (1 mol equiv) and then with methyl iodide
(1 mol equiv) according to a modified literature proce-
dure27,28 to afford the amino ester 4 in 53% isolated yield
after column chromatography. Introduction of the
fluorous ponytails was performed by the addition of
*
Corresponding author. Tel.: +33 (0)4 72448183; fax: +33 (0)4
78898914; e-mail: sinou@univ-lyon1.fr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.013

2966
J. Bayardon, D. Sinou / Tetrahedron: Asymmetry 16 (2005) 2965–2972
perfluorooctyl iodide to compound 4 in the presence of
AIBN29 to give the fluorous amino ester 5 as a mixture
of epimers in 71% yield, whose reaction with tributyltin
hydride in the presence of AIBN in trifluorotoluene at
80 ꢁC gave the fluorous amino ester 6 in 78% isolated
yield. Deprotection of the N-Boc was performed in the
followed by reduction of the ester function of the amino
ester using sodium borohydride in methanol,31 afforded
compounds 11 and 12 in 95% and 94% yields, respec-
tively. Condensation of amino alcohol 12 (2 mol equiv)
with malonimidate ethyl ester dihydrochloride in
CH2Cl2 at room temperature32 afforded the bis(oxazo-
line) 13 in 55% isolated yield. Treatment of bis(oxazo-
line) 13 with NaH (3 mol equiv) in DMF at 25 ꢁC,
followed by 1H,1H,2H,2H,3H,3H-perfluoroundecyl
iodide (2.3 mol equiv) in DMF at 80 ꢁC,24 afforded the
fluorous bis(oxazoline) 14 in 72% isolated yield. Oxygen
deprotection of compound 14 was carried out in ethanol
at reflux with Pd(OAc)2 and PPh3 in the presence
30
presence of CF3CO2H in CH2Cl2 to afford compound
7 in 92% yield. Reduction of the ester function of amino
ester 7 using sodium borohydride in methanol according
to the literature procedure31 gave the fluorous amino
alcohol 8 in 94% yield. Finally, condensation of amino
alcohol 8 (2 M equiv) with malonimidate ethyl ester
dihydrochloride in CH2Cl2 at room temperature32 affor-
ded the fluorous bis(oxazoline) 1 in 43% isolated yield.
Unfortunately, all attempts to introduce two other flu-
orous ponytails on the methylene position of this
bis(oxazoline) 1 by alkylation according to the method-
ology used previously24 were unsuccessful; we always
obtained a mixture of by-products whatever the condi-
tions used (Scheme 1).
25
of SiO2 to give fluorous bis(oxazoline) 15 in 72%
yield. The introduction of two other perfluoroalkyl
chains was achieved by alkylation of compound 15
with pentadecafluorooctyl nonafluorobutane sulfonate
C7F15CH2OSO2C4F15 in DMF at 80 ꢁC in the presence
of cesium carbonate.34 Fluorous bis(oxazoline) 21 bear-
ing four ponytails was thus obtained in 66% unopti-
mized yield (Scheme 2).
Thus, we turned our attention to another approach.
Treatment of (S)-N-Boc-tyrosine methyl ester 933 with
allyl bromide in DMF at room temperature in the pres-
ence of potassium carbonate as the base afforded the
amino ester 10 in 95% isolated yield. Sequential cleavage
of the N-Boc group using CF3CO2H in CH2Cl2,30
The fluorine contents of fluorous box ligands 1 and 2
were calculated as 56.9% and 59.3%, respectively. The
partition coefficients P (P = cFC72/corganic solvent) of com-
pounds 1 and 2 in CH2Cl2/FC72 (50:50, v/v) and
CH3CN/FC72 (50:50, v/v) were gravimetrically deter-
I
C8F17
C8F17
C8F17
C8F17
O
O
vi
vii
viii
O
OH
O
O
O
O
N
N
v
iv
i,ii,iii
CH2OH
CO2H
CO2CH3
CO2CH3
CO2CH3
CO2CH3
O
O
H2N
BocHN
H2N
BocHN
BocHN
BocHN
3
4
5
6
8
7
C8F17
C8F17
1
Scheme 1. Synthesis of bis(oxazoline) 1. Reagents and conditions: (i) NaH, DMF, 0 ꢁC; (ii) CH2@CH–CH2Br, rt; (iii) CH3I, rt; (iv) C8F17I, AIBN,
75 ꢁC; (v) AIBN, HSnBu3, C6H5CF3, 80 ꢁC; (vi) CF3CO2H, CH2Cl2, rt; (vii) NaBH4, CH3OH, 35 ꢁC; (viii) C2H5OC(NH)CH2C(NH)OC2H5, 2HCl,
CH2Cl2, rt.
O
OH
O
O
i
ii
iii
iv
CO2CH3
CO2CH3
CH2OH
CO2CH3
BocHN
BocHN
H2N
H2N
9
10
11
12
(CH2)3C8F17
C8F17(CH2)3
O
(CH2)3C8F17
O
C8F17(CH2)3
O
(CH2)3C8F17
O
C8F17(CH2)3
O
N
O
N
O
O
viii
v
vi, vii
N
N
N
N
N
N
O
O
OH
OH
O
C7F15CH2O
OCH2C7F15
O
2
15
13
14
Scheme 2. Synthesis of bis(oxazoline) 2. Reagents and conditions: (i) CH2@CH–CH2Br, K2CO3, Bu4NI, DMF, rt; (ii) CF3CO2H, CH2Cl2, rt; (iii)
NaBH4, CH3OH, 35 ꢁC; (iv) C2H5OC(NH)CH2C(NH)OC2H5, 2HCl, CH2Cl2, rt; (v) C8F17(CH2)3I, NaH, DMF, rt; (vi) Pd(OAc)2, PPh3, C2H5OH,
reflux; (vii) SiO2, C2H5OH, rt; (viii) C7F15CH2OSO2C4F9, CsCO3, DMF, 80 ꢁC.

J. Bayardon, D. Sinou / Tetrahedron: Asymmetry 16 (2005) 2965–2972
2967
CH(CO2Me)2
ded coupling product 16 in 98% conversion and 92%
ee (Table 1, entry 3).
OAc
Ph
Pd˚]/L*
(1)
Ph
Ph
Ph
CH2(CO2Me)2
16
The enantioselective allylic oxidation of cyclohexene
(Scheme 3, Eq. 2) was performed at 50 ꢁC in CHCl3/
CH3CN by forming the copper(I)triflate- or
copper(I)hexafluorophosphate-bis(oxazoline) (5 mol %)
and adding 80 equiv of cyclohexene followed by
20 equiv of tert-butyl perbenzoate. The catalyst
obtained from Cu(OTf) and ligand 1 and ligand 2 gave
cyclohexenyl benzoate 17 in 76% and 49% yield after
7 days at rt and 2 days at 50 ꢁC, respectively, and with
ee up to 43% and 50% ee (Table 1, entries 4 and 5).
The catalyst obtained by mixing [Cu(CH3CN)4]PF6
and ligand 2 only gave 12% yield after 3 days (Table 1,
entry 7). Moreover, evaporation of the solvents using
Cu(OTf) as the copper precursor and ligand 2, followed
by the addition of hexane, allowed the precipitation of
the complex; this precipitated complex was reused in
another allylic oxidation to give the allylic benzoate 17
in 43% yield and 50% ee after 2 days (Table 1, entry
6). The recycling of this catalyst gave higher conversion
with similar ee than the previously described fluorous
bis(oxazolines).24
OCOPh
PhCO3-tert-Bu
CuOTf/L*
(2)
17
Cu(OTf)2/L*
OH
CO2Et
(3)
+
CHO-CO2Et
Ph
Me
Ph
18
Scheme 3. Enantioselective reactions catalyzed by metal complexes of
fluorous box ligands 1 and 2.
mined as ca. 0.5 and 2.0, and 4.3 and 12.3, respectively.
These values clearly show that bis(oxazoline) 2, which
has a fluorine content of 56.9% and bears four fluorous
ponytails is more soluble in the fluorous solvent than
bis(oxazoline) 1, which bears only two fluorous
ponytails.
Ligands 1 and 2 were tested in the representative enan-
tioselective transformations reported in Scheme 3 (Eqs.
1, 2, and 3). The results are shown in Table 1.
Finally, the ene reaction between a-methylstyrene and
ethyl glyoxalate (Scheme 3, Eq. 3) was carried out from
0 ꢁC to room temperature for 24 h in CH2Cl2 in the
presence of [Cu(OTf)2] and ligand 2 to afford adduct
18 in 32% yield and only 5% ee (Table 1, entry 8).
These ligands were first assessed in the palladium-catal-
yzed allylic substitution of rac-(E)-1,3-diphenylpropenyl
acetate with dimethyl malonate (Scheme 3, Eq. 1). The
reaction was carried out in CH2Cl2 at rt in the presence
of ligand 1 and [Pd(g3-C3H5)Cl]2 (5 mol %), with BSA/
KOAc being used as the base, to afford adduct 16 with
only 39% conversion and 80% ee (Table 1, entry 1).
When the same reaction was repeated using ligand 2,
the conversion was quantitative and the ee increased
to 92% (Table 1, entry 2), quite close to the values ob-
tained previously using similar fluorous bis(oxazo-
lines).24 Moreover, evaporation of the solvent at the
end of the last reaction, followed by liquid–liquid extrac-
tion using FC72 as the fluorous solvent, allowed the
quantitative recovery of bis(oxazoline) 2; the reuse of
this recovered ligand in another allylic alkylation affor-
3. Conclusion
In conclusion, two new chiral fluorous bis(oxazolines)
with a fluorous content of 56.9% and 59.3%, respec-
tively, have been prepared starting from (S)-serine and
(S)-tyrosine, the latter bearing four fluorous ponytails.
Applications of these fluorous box ligands in asymmet-
ric alkylation gave ee up to 92%, and in allylic oxidation
ee up to 50%. Recycling and reuse of the ligand bearing
the four ponytails (%F = 59.3%) in asymmetric alkyl-
ation, and of the catalytic system in allylic oxidation
are now effective, the same enantioselectivities being
obtained.
Table 1. Enantioselective reaction catalyzed by fluorous box ligands 1 and 2
Entry
Equation in Scheme 3
Catalyst
Solvent
Time (h)
Yield (%)
ee (%) (config.)a
1
2
1
1
1
2
2
2
2
3
[Pd(g3-C3H5)Cl]2/1
[Pd(g3-C3H5)Cl]2/2
[Pd(g3-C3H5)Cl]2/2
CuOTfÆ0.5C6H6/1
CuOTfÆ0.5C6H6/2
CuOTfÆ0.5C6H6/2
[Cu(CH3CN)4]PF6/2
Cu(OTf)2/2
CH2Cl2
CH2Cl2
CH2Cl2
24
24
24
168
48
48
39b (16)
98b (16)
98b (16)
76 (17)
49 (17)
43 (17)
12 (17)
32 (18)
80 (S)
92 (S)
92 (S)
43 (S)
50 (S)
50 (S)
nd
2 Bisc
3
4d
CHCl3/CH3CN
CHCl3/CH3CN
CHCl3/CH3CN
FC72/CH3CN
4 Bisd,e
5d
6
72
24
f
CH2Cl2
5 (R)
a The ee values were determined by HPLC using a chiral column Chiralpak AD, and the absolute configuration was determined by comparison of the
HPLC retention time with the literature data.
b The conversion was determined by GC.
c Recycling of the ligand by liquid extraction.
d Reaction performed at 50 ꢁC.
e Recycling of the catalyst by precipitation with hexane.
f THF (0.5 mL) was added.

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J. Bayardon, D. Sinou / Tetrahedron: Asymmetry 16 (2005) 2965–2972
4. Experimental
52.8, 54.4, 70.3, 72.6, 80.3, 117.7, 134.4, 155.5, 171.6.
Anal. Calcd for C12H21NO5: C, 55.58; H, 8.16. Found:
C, 55.21; H, 7.95.
4.1. General
Melting points were determined on a Buchi melting point
apparatus and are uncorrected. Optical rotations were
measured on a Perkin Elmer Model 241 polari-
meter. The NMR spectra (1H: 300 MHz, 13C: 75 MHz,
19F: 282 MHz) were recorded on a Bruker AM 300
instrument with Me4Si, CDCl3, and CFCl3 as the inter-
nal standard, respectively. Exact mass spectra were
recorded on a Finnigan Mat 95 XL spectrometer.
Column chromatography was performed on silica gel
60 (230–240 mesh, Merck). The reactions involving
organometallic catalysis were carried out in a Schlenk
tube under an inert atmosphere.
4.4. (S)-N-Boc-O-(1H,1H,2H,3H,3H-2-iodo-perfluo-
roundecanyl)serine methyl ester 5
A mixture of (S)-serine methyl ester 4 (1.3 g, 5 mmol),
perfluorooctyl iodide (2.7 g, 5 mmol), and AIBN
(41.1 mg, 0.25 mmol) was warmed at 75 ꢁC for 1 h.
After being cooled at rt, AIBN (41.1 mg, 0.25 mmol)
was added again and the mixture warmed at 75 ꢁC for
1 h. This experiment was done once more and the
mixture warmed for 24 h. After being cooled to rt, the
mixture was directly purified by column chromato-
graphy on silica gel, using a 4:1 mixture of petroleum
ether/ethyl acetate as the eluent to give fluoro amino es-
The solvents were purified by standard procedures, and
commercial products used as received. Pentadecafluo-
rooctyl nonafluorobutane sulfonate34 and (S)-N-Boc-
tyrosine methyl ester 933 were prepared according to
the literature procedure.
ter 5 (2.86 g, 71% yield) as a white solid. Mp 68–70 ꢁC;
25
Rf 0.58 (petroleum ether/ethyl acetate 4:1); ½aŠ ¼ þ11.3
D
(c 0.6, CHCl3). 1H NMR (CDCl3): d 1.46 and 1.47
(2 · s, 9H, CH3), 2.71–3.00 (m, 2H, CH2CF2), 3.74–
3.82 (m, 3H, CH2O), 3.76 and 3.78 (2 · s, 3H, OCH3),
3.95 (m, 1H, CH2O), 4.36 (m, 1H, CHI), 4.51 (m, 1H,
CHN), 5.51 (br s, 1 H, CHN); 13C NMR (CDCl3): d
13.9, 14.1, 28.2, 28.3, 37.7 (t, J = 22.3 Hz), 52.4, 52.5,
54.1, 71.2, 71.3, 75.9, 76.0, 80.1, 110.9–119.2, 155.6,
155.7, 170.9; 19F NMR (CDCl3): d À127.3 (m, 2F),
À124.5 (m, 2F), À123.0 (m, 2F), À122.6 (m, 6F),
À114.6 (m, 2F), À82.2 (t, J = 9.3 Hz, 3F). Anal. Calcd
for C20H21F17INO5: C, 29.83; H, 2.63. Found: C,
29.74; H, 2.62.
4.2. (S)-N-Boc-serine 3
Di-tert-butyl dicarbonate (2.4 g, 11 mmol) in dioxane
(10 mL) was added at 0 ꢁC to a solution of (S)-serine
(1 g, 9.5 mmol) in aqueous 1 M NaOH (10 mL). After
being stirred at rt for 3 h, an aqueous 1 M solution of
KHSO4 (10 mL) was added at 0 ꢁC. The aqueous phase
was extracted with ethyl acetate (3 · 20 mL), and the
combined organic phases were dried over Na2SO4.
Evaporation of the solvent gave (S)-N-Boc-serine 3
4.5. (S)-N-Boc-O-(1H,1H,2H,2H,3H,3H-perfluoroun-
decanyl)serine methyl ester 6
25
(1.91 g, 98% yield) as an oil. ½aŠ ¼ À3.2 (c 1.8,
D
1
CH3CO2H); H NMR (CDCl3): d 1.45 (s, 9H, CH3),
3.86 (m, 1H, CH2O), 4.03 (m, 1H, CH2O), 4.37 (m,
1H, CHN), 5.83 (br s, 1H, NH). These physical data
are in agreement with those published previously.26
To a mixture of iodo derivative 5 (2.8 g, 3.48 mmol) and
AIBN (52.2 mg, 0.35 mmol) in C6H5CF3 (15 mL) was
added under argon HSnBu3 (1.4 mL, 5.22 mmol). After
being stirred for 3 h at 80 ꢁC, the solvent was evaporated
and the residue purified by column chromatography on
silica gel, using a 4:1 mixture of petroleum ether/ethyl
acetate as the eluent to give fluoro amino ester 6
4.3. (S)-O-Allyl-N-Boc-serine methyl ester 4
To a solution of amino ester 3 (1.92 g, 9.4 mmol) in
DMF (20 mL) was added NaH (0.49 mg, 20.6 mmol).
After being stirred for 30 min at 0 ꢁC, allyl bromide
(0.77 mL, 8.9 mmol) was added and the solution was
stirred at 0 ꢁC for 5 min, then at rt for 3 h. Methyl iodide
(0.74 mL, 11.9 mmol) was added and the reaction stirred
at rt for 1 h. The addition of a saturated aqueous solu-
tion of NaCl (30 mL) gave a solid that was filtered.
The filtrate was extracted with diethyl ether
(3 · 20 mL), and the combined organic phases were
washed with a saturated aqueous solution of NaCl
(20 mL). Evaporation of the solvent gave a residue that
was purified by column chromatography on silica gel,
using a 4:1 mixture of petroleum ether/ethyl acetate as
the eluent to give (S)-serine methyl ester 4 (1.29, 53%
yield) as an oil. Rf 0.64 (petroleum ether/ethyl acetate
(1.84 g, 78% yield) as an oil. Rf 0.48 (petroleum ether/
25
ethyl acetate 4:1); ½aŠ ¼ þ10.9 (c 0.6, CHCl3); 1H
NMR (CDCl3): d 1.46D(s, 9H, CH3), 1.86–1.89 (m, 2H,
CH2), 2.12–2.15 (m, 2H, CH2CF2), 3.51–3.57 (m, 2H,
CH2O), 3.70 (dd, J = 9.4, 3.0 Hz, 1H, CH2O), 3.75 (s,
3H, OCH3), 3.85 (dd, J = 9.4, 3.0 Hz, 1H, CH2O),
4.50 (m, 1H, CHN), 5.48 (br s, 1 H, CHN); 13C NMR
(CDCl3): d 20.7, 27.8 (t, J = 21.6), 28.2, 52.2, 54.1,
69.8, 70.9, 80.0, 115.4–118.7, 155.7, 171.2; 19F NMR
(CDCl3): d À127.4 (m, 2F), À124.5 (m, 2F), À123.9
(m, 2F), À122.9 (m, 6F), À115.5 (m, 2F), À82.3 (t,
J = 9.3 Hz, 3F). Anal. Calcd for C20H22F17NO5: C,
35.36; H, 3.26. Found: C, 35.60; H, 3.20.
4.6. (S)-O-(1H,1H,2H,2H,3H,3H-Perfluoroundecanyl)-
serine methyl ester 7
25
D
1
4:1); ½aŠ ¼ þ16.9 (c 0.4, CHCl3); H NMR (CDCl3):
d 1.46 (s, 9H, CH3), 3.64 (dd, J = 9.5, 3.4 Hz, 1H,
CH2O), 3.76 (s, 3H, OCH3), 3.85 (dd, J = 9.5, 3.4 Hz,
1H, CH2O), 3.96–3.98 (m, 2H, OCH2), 4.42 (m, 1 H,
CHN), 5.17–5.27 (m, 2H, @CH2), 5.36 (br s, 1H, NH),
5.77–5.90 (m, 1H, –CH@); 13C NMR (CDCl3): d 28.7,
To a solution of fluorous amino ester 6 (2.33 g,
3.42 mmol) in CH2Cl2 (10 mL) was slowly added tri-
fluoroacetic acid (3.8 mL, 21.8 mmol). After being
stirred for 1 h at rt, the solvent was evaporated, and a

J. Bayardon, D. Sinou / Tetrahedron: Asymmetry 16 (2005) 2965–2972
2969
saturated aqueous solution of NaHCO3 (10 mL) added.
The aqueous phase was extracted with CH2Cl2
(3 · 20 mL), and the combined organic phases dried
over Na2SO4. Evaporation of the solvent gave a residue
that was purified by column chromatography on silica
gel, using a 9:1 mixture of CH2Cl2/CH3OH as the eluent
d 21.0, 28.1 (t, J = 22.3), 28.5, 66.3, 70.1, 71.1, 72.7,
107.4–115.5, 163.5; 19F NMR (CDCl3): d À126.6
(m, 4F), À123.9 (m, 4F), À123.2 (m, 4F), À122.4 (m,
12F), À114.8 (m, 4F), À81.2 (t, J = 10.3 Hz, 6F). Anal.
Calcd for C31H24F34N2O4: C, 32.82; H, 2.13. Found: C,
33.08; H, 2.03.
to give (S)-serine methyl ester 7 (1.82 g, 92% yield) as an
25
D
oil. Rf 0.54 (CH2Cl2/CH3OH 9:1); ½aŠ ¼ þ1.8 (c 0.4,
4.9. (S)-O-Allyl-N-Boc-tyrosine methyl ester 10
1
CHCl3); H NMR (CDCl3): d 1.81 (br s, 2H, NH2),
1.85–1.92 (m, 2H, CH2), 2.03–2.25 (m, 2H, CH2CF2),
3.48–3.60 (m, 2H, CH2O), 3.62–3.72 (m, 3H, CH2O),
3.74 (s, 3H, OCH3); 13C NMR (CDCl3): d 20.7, 27.9
(t, J = 22.3), 52.1, 55.0, 69.9, 72.9, 108.9–119.3, 174.4;
19F NMR (CDCl3): d À127.4 (m, 2F), À124.6 (m, 2F),
À124.0 (m, 2F), À123.1 (m, 6F), À115.6 (m, 2F),
À82.3 (t, J = 10.3 Hz, 3F). Anal. Calcd for
C15H14F17NO3: C, 31.10; H, 2.44. Found: C, 30.79; H,
2.08.
A mixture of (S)-N-Boc-tyrosine methyl ester 933
(2.39 g, 8.11 mmol), K2CO3 (2.23 g, 16.1 mmol), Bu4NI
(0.3 g, 0.81 mmol), and allyl bromide (0.84 mL,
9.73 mmol) in DMF (20 mL) was stirred at rt for 18 h.
After the addition of a 1 M aqueous solution of KHSO4
(20 mL), the product was extracted with ethyl acetate
(3 · 10 mL). The organic phase was washed with a satu-
rated aqueous solution of NaHCO3 (20 mL), an aque-
ous saturated solution of NaCl (20 mL), and then
dried over Na2SO4. Evaporation of the solvent afforded
4.7. (R)-2-Amino-3-[(1H,1H,2H,2H,3H,3H-perfluoro-
undecanyl)oxy]-propan-2-ol 8
amino ester 10 (2.58 g, 95% yield) as an oil. Rf 0.4 (ethyl
25
acetate/petroleum ether 1:5); ½aŠ ¼ þ48.8 (c 1, CHCl3);
D
1H NMR (CDCl3): d 1.42 (s, 9H, CH3), 3.00–3.02 (m,
2H, CH2Ph), 3.71 (s, 3H, OCH3), 4.51 (m, 1H, CHN),
4.51 (d, J = 5,5 Hz, 2H, OCH2), 4.95 (br s, 1H, NH),
5.28 (dd, J = 11.3, 1.5 Hz, 1H, CH@CH2), 5.40 (dd,
J = 17.3, 1.5 Hz, 1H, CH@CH2), 6.05 (m, 1H,
CH@CH2), 6.85 (d, J = 8.7 Hz, 2H, Harom), 7.03 (d,
J = 8.7 Hz, 2H, Harom); 13C NMR (CDCl3): d 28.7,
37.9, 52.6, 54.9, 69.2, 80.3, 115.2, 118.0, 128.5, 130.7,
133.7, 155.8, 158.1, 172.8. Anal. Calcd for C18H25NO5:
C, 64.46; H, 7.51. Found: C, 64.42; H, 7.59.
To a solution of compound 7 (2.06 g, 3.56 mmol) in
CH3OH (15 mL) was added NaBH4 (0.54 g,
14.25 mmol). After being stirred for 2 h at 35 ꢁC, water
was added, and the methanol was evaporated. The aque-
ous phase was extracted with CHCl3 (3 · 20 mL), and
chloroform solution was dried over Na2SO4. Evapora-
tion of the solvent under reduced pressure gave a residue
that was purified by column chromatography on silica
gel, using a 2:1 mixture of CH2Cl2/CH3OH as the eluent
to afford 8 (1.84 g, 94% yield) as a yellow solid. Mp 62–
25
D
64 ꢁC; Rf 0.26 (CH2Cl2/CH3OH 2:1); ½aŠ ¼ þ0.6 (c 0.5,
4.10. (S)-O-Allyl-tyrosine methyl ester 11
CHCl3); 1H NMR (CDCl3): d 1.76 (br s, 3H, NH2, OH),
1.84–1.94 (m, 2H, CH2), 2.12–2.21 (m, 2H, CH2CF2),
3.09 (m, 1H, CHN), 3.37–3.54 (m, 5H, CH2O), 3.63
(m, 1H, CH2O); 13C NMR (CDCl3): d 19.7, 26.9 (t,
J = 22.3), 51.4, 63.1, 68.8, 72.4, 110.1–118.7; 19F NMR
(CDCl3): d À126.8 (m, 2F), À124.0 (m, 2F), À123.3
(m, 2F), À122.5 (m, 6F), À115.0 (m, 2F), À81.5 (t,
J = 10.3 Hz, 3F). Anal. Calcd for C14H14F17NO2: C,
30.50; H, 2.56. Found: C, 30.10; H, 2.60.
T o S()-O-allyl-N-Boc-tyrosine methyl ester 10 (1.40 g,
4.18 mmol) dissolved in CH2Cl2 (15 mL) was slowly
added CF3CO2H (4.6 mL, 26.3 mmol). After being stir-
red for 1 h at rt, the solvent was evaporated, and a sat-
urated aqueous solution of NaHCO3 (10 mL) added.
The aqueous solution was extracted with CH2Cl2
(3 · 20 mL). Evaporation of the solvent under reduced
pressure gave a residue that was purified by column
chromatography on silica gel, using ethyl acetate as
4.8. (4S,40S)-2,20-Methylene-bis[4-{(1H,1H,2H,2H,
3H,3H-perfluoroundecanyl)oxy} methyl]-4,5-dihydro-
1,3-oxazole 1
the eluent to give compound 11 (930 mg, 95% yield) as
25
D
a yellow oil. Rf 0.36 (ethyl acetate); ½aŠ ¼ þ10 (c 1,
1
CHCl3); H NMR (CDCl3): d 1.50 (br s, 2H, NH2),
2.81 (dd, J = 13.6, 7.7 Hz, 1H, CH2Ph), 3.02 (dd,
J = 13.6, 5.2 Hz, 1H, CH2Ph), 3.68 (m, 1H, CHN),
3.72 (s, 3H, OCH3), 4.51 (d, J = 5.3 Hz, 2H, OCH2),
5.29 (dd, J = 10.4, 1.3 Hz, 1H, CH@CH2), 5.40 (dd,
J = 17.3, 1.3 Hz, 1H, CH@CH2), 6,05 (m, 1H,
CH@CH2), 6.85 (d, J = 8,7 Hz, 2H, Harom), 7.09 (d,
J = 8.7 Hz, 2H, Harom); 13C NMR (CDCl3): d 40.6,
52.3, 56.3, 69.2, 115.2, 118.0, 129.7, 130.6, 133.7,
157.9, 175.9. Anal. Calcd for C13H17NO3: C, 66.36; H,
To a solution of fluorous amino alcohol 8 (2.31 g,
4.2 mmol) in CH2Cl2 (20 mL) was added diethyl malo-
nimidate dihydrochloride (0.49 g, 2.15 mmol) portion-
wise over 10 min. After being stirred at rt for 48 h, the
solution was poured into water (20 mL), and the mix-
ture extracted with CH2Cl2 (3 · 20 mL). The organic
layers were washed with brine (20 mL), dried over
Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography
on silica gel, using a 9:1 mixture of CH2Cl2/CH3OH
as the eluent to afford bis(oxazoline) 1 (1.24 g, 43%
yield) as a yellow solid. Mp 52–54 ꢁC; Rf 0.74
1
7.28. Found: C, 66.24; H, 7.23. The H NMR data are
in agreement with those published previously.35
4.11. (S)-3-[4-Allyloxyphenyl]-2-aminopropanol 12
25
1
(CH2Cl2/CH3OH 9:1); ½aŠ ¼ À8.3 (c 0.2, CHCl3); H
D
NMR (CDCl3): d 1.81–1.83 (m, 4H, CH2), 2.08–2.13
(m, 4H, CH2CF2), 3.33–3.68 (m, 10H, CH2, CH2O),
4.13–4.36 (m, 6H, OCH2, CHN); 13C NMR (CDCl3):
To a solution of compound 11 (840 mg, 3.56 mmol) in
CH3OH (15 mL) was added NaBH4 (0.54 g, 14.25
mmol). After being stirred for 2 h at 35 ꢁC, water was

2970
J. Bayardon, D. Sinou / Tetrahedron: Asymmetry 16 (2005) 2965–2972
added, and the methanol evaporated. The aqueous
phase was extracted with CHCl3 (3 · 20 mL), and the
chloroform solution was dried over Na2SO4. Evapora-
tion of the solvent under reduced pressure gave a residue
that was purified by column chromatography on silica
gel, using a 4:1 CH2Cl2/CH3OH mixture to give amino
alcohol 12 (650 mg, 88% yield) as a white solid. Mp
76–78 ꢁC [lit36 mp 77–79 ꢁC]; Rf 0.26 (CH2Cl2/CH3OH
Na2SO4. Evaporation of the solvent under reduced pres-
sure gave a residue that was purified by flash-chroma-
tography on silica gel, using ethyl acetate/petroleum
ether (2:1) as the eluent to give the fluorous bis(oxazo-
line) 14 (748 mg, 57% yield) as an oil. Rf 0.44 (petroleum
25
1
ether/ethyl acetate 2:1); ½aŠ ¼ À9.7 (c 1.0, CHCl3); H
D
NMR (CDCl3): d 1.53–1.56 (m, 4H, CH2), 2.04–2.10
(m, 8H, CH2, CH2CF2), 2.60 (dd, J = 13.7, 8.3 Hz,
2H, CH2Ph), 3.30 (dd, J = 13.7, 4.9 Hz, 2H, CH2Ph),
3.98–4.02 (m, 2H, CH2O), 4.16–4.22 (m, 2H, CH2O),
4.37–4.40 (m, 2H, CHN), 4.49 (d, J = 5.1 Hz,
4H, OCH2–CH@), 5.26 (dd, J = 10.4, 1.3 Hz, 2H,
–CH@CH2), 5.39 (dd, J = 17.2, 1.3 Hz, 2H,
–CH@CH2), 5.98–6.10 (m, 2H, –CH@CH2), 6.84 (d,
J = 8.7 Hz, 4H, Harom), 7.10 (d, J = 8.7 Hz, 4H, Harom);
13C NMR (CDCl3): d 15.6, 31.3 (t, J = 21.0 Hz), 33.2,
40.9, 46.0, 67.7, 69.1, 72.2, 115.1, 117.8, 130.0, 130.7,
133.7, 157.7, 167.2; 19F NMR (CDCl3): d À127.0 (m,
4F, CF2), À124.2 (m, 4F, CF2), À123.5 (m, 4F, CF2),
À122.7 (m, 12F, CF2), À114.9 (m, 4F, CF2), À81.7 (t,
J = 9.3 Hz, 6F, CF3). Anal. Calcd for C49H40F34N2O4
(1366.8): C, 43.06; H, 2.95. Found: C, 43.08; H, 3.02.
25
1
4:1); ½aŠ ¼ À14.5 (c 1, CHCl3); H NMR (300 MHz):
D
d 1.80 (br s, 3H, NH2, OH), 2.46 (dd, J = 13.6, 8.7 Hz,
1H, CH2Ph), 3.07 (dd, J = 13.6, 5.3 Hz, 1H, CH2Ph),
3.07 (m, 1H, CHN), 3.38 (dd, J = 10.5, 7.2 Hz, 1H,
CH2OH), 3.62 (dd, J = 10.5, 3.8 Hz, 1H, CH2OH),
4.51 (d, J = 5.3 Hz, 2H, OCH2), 5.27 (dd, J = 10.6,
1.5 Hz, 1H, CH@CH2), 5.41 (dd, J = 17.0, 1.5 Hz, 1H,
CH@CH2), 6.05 (m, 1H, CH@CH2), 6.85 (d,
J = 8.6 Hz, 2H, Harom), 7.10 (d, J = 8.6 Hz, 2H, Harom);
13C NMR (CDCl3): d 40.3, 54.6, 66.6, 69.2, 115.2, 118.0,
130.5, 131.2, 133.7, 157.6. HRMS: Calcd for
C12H18NO2 [M + H]+: 208.1338. Found: 208.1333.
4.12. (4S,40S)-2,20-Methylenebis[4-(4-allyloxybenzyl)-
4,5-dihydro-1,3-oxazole] 13
4.14. (4S,40S)-2,20-(1H,1H,2H,2H,3H,3H-Perfluoro-
tricosane-12,12-diyl)bis-[4-(4-hydroxy benzyl)-4,5-
dihydro-1,3-oxazole] 15
To amino alcohol 12 (700 mg, 3.38 mmol) dissolved in
CH2Cl2 (10 mL) was slowly added malonimidate ethyl
ester dihydrochloride (390 mg, 1.72 mmol). After being
stirred for 48 h at rt, water (10 mL) was added and the
organic product extracted with CH2Cl2 (3 · 10 mL).
The organic phase was washed with a saturated aqueous
solution of NaCl (20 mL), and dried over Na2SO4.
Evaporation of the solvent under reduced pressure gave
a residue that was purified by flash-chromatography on
silica gel, using ethyl acetate as the eluent to afford
A mixture of fluorous bis(oxazoline) 14 (770 mg,
0.56 mmol), Pd(OAc)2 (23.5 mg, 0.11 mmol), and PPh3
(130 mg, 0.50 mmol) in ethanol (10 mL) was refluxed
for 1.5 h. After cooling, SiO2 (1.13 g) was added and
the resulting mixture stirred for 45 min at rt. Filtration
over Celite followed by evaporation of the solvent gave
a residue that was purified by flash-chromatography on
silica gel, using ethyl acetate/petroleum ether (1:1) as the
eluent to give the fluorous bis(oxazoline) 15 (518 mg,
72% yield) as a yellow solid. Mp 67–69 ꢁC; Rf 0.6 (petro-
leum ether/ethyl acetate 1:1); [a]D = À19.3 (c 1.02, ace-
tone); 1H NMR (CD3COCD3): d 1.48–1.52 (m, 4H,
CH2), 1.89–1.95 (m, 4H, CH2), 2.06–2.19 (m, 4H,
CH2CF2), 2.46 (dd, J = 13.9, 7.6 Hz, 2H, CH2Ph), 2.73
(dd, J = 13.9, 6.0 Hz, 2H, CH2Ph), 3.80–3.86 (m, 2H,
CH2O), 4.05–4.11 (m, 2H, CH2O), 4.14–4.22 (m, 2H,
CHN), 6.62 (d, J = 8.6 Hz, 4H, Harom), 6.95 (d,
J = 8.6 Hz, 4H, Harom); 13C NMR (CD3COCD3): d
16.5, 31.8 (t, J = 22.0 Hz), 34.1, 41.8, 46.8, 68.7, 72.9,
116.3, 130.1, 131.6, 157.2, 167.7; 19F NMR
(CD3COCD3): d À126.6 (m, 4F, CF2), À123.9 (m, 4F,
CF2), À123.2 (m, 4F, CF2), À122.3 (m, 12F, CF2),
À114.6 (m, 4F, CF2), À81.2 (m, 6F, CF3). Anal. Calcd
for C43H32F34N2O4: C, 40.12; H, 2.51. Found: C,
40.32; H, 2.57.
bis(oxazoline) 13 (377 mg, 55% yield) as an oil. Rf 0.51
25
(CH2Cl2/CH3OH 9:1); ½aŠ ¼ À16.9 (c 1.0, CHCl3);
D
1H NMR (CDCl3): d 2.62 (dd, J = 13.8, 8.3 Hz, 2H,
CH2Ph), 3.02 (dd, J = 13.8, 5.3 Hz, 2H, CH2Ph), 3.31
(s, 2H, CH2), 3.97–4.02 (m, 2H, CH2O), 4.19–4.25
(m, 2H, CH2O), 4.34–4.41 (m, 2H, CHN), 4.50
(d, J = 5.3 Hz, 4H, OCH2–CH@), 5.27 (dd, J = 10.5,
1.5 Hz, 2H, –CH@CH2), 5.39 (dd, J = 17.2, 1.5 Hz,
2H, –CH@CH2), 6.00–6.09 (m, 2H, –CH@CH2), 6.83
(d, J = 8.5 Hz, 4H, Harom), 7.10 (d, J = 8.5 Hz, 4H,
Harom); 13C NMR (CDCl3): d 28.8, 40.9, 67.9, 69.2,
72.6, 115.1, 118.0, 130.3, 130.6, 133.8, 157.7, 162.4.
Anal. Calcd for C27H30N2O4: C, 72.62; H, 6.77. Found:
C, 72.44; H, 6.84.
4.13. (4S,40S)-2,20-(1H,1H,2H,2H,3H,3H-Perfluorotric-
osane-12,12-diyl)bis[4-(4-allyloxy benzyl)-4,5-dihydro-
1,3-oxazole] 14
Bis(oxazoline) 13 (430 mg, 0.96 mmol) dissolved in
DMF (4 mL) was slowly added at 0 ꢁC to a suspension
of NaH (69 mg, 2.86 mmol) in dry DMF (8 mL). After
being stirred for 1 h at rt, C8F17(CH2)3I (1.29 g,
2.19 mmol) in DMF (4 mL) was slowly added. After
being stirred at 80 ꢁC for 16 h, half of the solvent was
evaporated, and water (10 mL) added. The organic
product was extracted using diethyl ether (4 · 10 mL),
and the ether solution was washed with a saturated
aqueous solution of NaCl (2 · 20 mL), and dried over
4.15. (4S,40S)-2,20-(1H,1H,2H,2H,3H,3H-Perfluorotric-
osane-12,12-diyl)bis-[4-(4-(1H,1H-perfluoroctyloxybenz-
yl))-4,5-dihydro-1,3-oxazole] 2
A mixture of bis(oxazoline) 15 (450 mg, 0.35 mmol),
pentadecafluorooctyl
nonafluorobutane
sulfonate
(610 mg, 0.90 mmol), and CsCO3 (380 mg, 1.17 mmol)
in dry DMF (7 mL) was stirred at 80 ꢁC for 18 h. After
cooling to rt, water (10 mL) was added, the aqueous
phase extracted with diethyl ether (3 · 10 mL), and the

J. Bayardon, D. Sinou / Tetrahedron: Asymmetry 16 (2005) 2965–2972
2971
organic phase dried over Na2SO4. Evaporation of the
solvent under reduced pressure gave a residue that was
dissolved in FC72 (10 mL). The fluorous phase was
washed with ethanol (2 · 10 mL), and acetonitrile
(2 · 10 mL). Evaporation of the fluorous solvent gave
the fluorous bis(oxazoline) 2 (474 mg, 66% yield) as a
brown solid. Mp 65–67 ꢁC; Rf 0.32 (petroleum ether/
1.28 mmol) in CH3CN (2 mL) was added to the solution
cooled at rt, followed by dropwise addition of tert-butyl
perbenzoate (61.3 mg, 0.32 mmol). The resulting solu-
tion was then stirred at rt for the time indicated. The
mixture was then diluted with ether (10 mL), and the or-
ganic solution was washed with water (5 mL), HCl 2 N
(5 mL), and water (5 mL). The solvent was removed in
vacuo to afford a residue that was purified by column
chromatography on silica gel, to give the corresponding
allylic benzoate 17. The ee was determined by HPLC
using a Chiralpak AD column (25 cm · 0.46 cm) and
eluting with hexane/i-PrOH (150:1).
25
1
ethyl acetate 2:1); ½aŠ ¼ À21.6 (c 0.5, C6H5CF3); H
D
NMR (CDCl3): d 1.56–1.59 (m, 4H, CH2), 1.94–2.06
(m, 8H, CH2, CH2CF2), 2.71 (dd, J = 13.8, 7.4 Hz,
2H, CH2Ph), 2.94 (dd, J = 13.8, 5.5 Hz, 2H, CH2Ph),
3.94–3.99 (m, 2H, CH2O), 4.18–4.24 (m, 2H, CH2O),
4.41 (t, J = 12.8 Hz, 4H, OCH2CF2), 4.37–4.45 (m,
2H, CHN), 6.85 (d, J = 8.5 Hz, 4H, Harom), 7.14 (d,
J = 8.5 Hz, 4H, Harom); 13C NMR (CDCl3): d 15.6,
31.6 (t, J = 22.8 Hz), 33.6, 40.7, 46.0, 65.6 (t,
J = 26.5 Hz), 67.4, 72.0, 115.2, 131.1, 131.9, 156.7,
161.7; 19F NMR (CDCl3): d À126.8 (m, 8F, CF2),
À124.1 (m, 8F, CF2), À124.0 (m, 8F, CF2), À122.6
(m, 20F, CF2), À120.2 (m, 4F, CF2), À114.7 (m, 4F,
CF2), À81.4 (t, J = 9.3 Hz, 12F, CF3). Anal. Calcd for
C59H34F64N2O4: C, 34.55; H, 1.67. Found: C, 34.53;
H, 1.90.
4.17.1. Recycling of the catalyst. After the reaction, the
solvent was removed and hexane (3 · 2 mL) added. The
catalyst, which precipitated as a blue-green solid, was
recovered by simple decantation of the supernatant
liquid. The catalyst was reused in another catalytic oxi-
dation without further addition of copper or ligand.
Evaporation of hexane afforded a residue that was puri-
fied by chromatography on silica, to give the allylic ben-
zoate 17.
4.18. General procedure for the catalytic ene reaction
4.16. General procedure for the catalytic allylic alkylation
To a solution of Cu(OTf)2 (11.2 mg, 31 lmol, 10 mol %)
in CH2Cl2 (2 mL) was added the fluorous bis(oxazoline)
2 (63.6 mg, 31 lmol, 10 mol %). After being stirred for
3 h, a-methylstyrene (39 lL, 0.3 mmol) and a 50% solu-
tion of ethyl glyoxalate (0.60 mL, 3 mmol) in toluene
were added. After being stirred for 24 h at rt, the solvent
was evaporated, and the residue purified by column
chromatography on silica gel, using petroleum ether/
ethyl acetate (2:1) as the eluent. The ee of compound
18 was determined by HPLC using a Chiralpak AD col-
umn (25 cm · 0.46 cm) and eluting with hexane/i-PrOH
(95:5).
Ligand (31.2 lmol, 6.5 mol %) and [Pd(g3-C3H5)Cl]2
(4.6 mg, 12.5 lmol, 2.5 mol %) were dissolved in the sol-
vent (1.5 mL) under nitrogen in a Schlenk tube. The
reaction mixture was stirred for 1 h at 50 ꢁC, and rac-
(E)-1,3-diphenyl-2-propenyl acetate (126 mg, 0.5 mmol)
in the solvent (1.5 mL) was transferred to this Schlenk
tube. After 20 min, this solution was transferred into
another reaction vessel containing N,O-bis(trimethyl-
silyl)acetamide (305 mg, 1.5 mmol), KOAc (4.9 mg,
0.05 mmol), and the nucleophile (1.5 mmol) in the corre-
sponding solvent (2 mL). The reaction mixture was
stirred at the desired temperature for the appropriate
time. The mixture was then diluted with diethyl ether,
and the organic layer was washed with a saturated aque-
ous NH4Cl solution (2 · 5 mL), and then dried over
Na2SO4. Evaporation of the solvent under a reduced
pressure gave a residue that was purified by chromato-
graphy on silica gel affording the alkylated product 16.
The enantioselectivity was determined by HPLC using
a Chiralpak AD column (25 cm · 0.46 cm) and eluting
with hexane/i-PrOH (6:4).
Acknowledgements
One of us (J.B.) thanks the French Ministry of Educa-
tion for a fellowship.
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