Catalytic enantioselective cyclopropanation of allylic alcohols using recyclable fluorous disulfonamide ligand

Article abstract of DOI:10.1016/j.tetlet.2008.07.125

Cyclopropanation of allylic alcohols with Et₂Zn and CH₂I₂ in the presence of a catalytic amount of fluorous disulfonamide 3 afforded the corresponding cyclopropylmethanols in 69-96% yield with 49-83% ee. The fluorous ligand 3 was readily recovered from the reaction mixture by the fluorous solid-phase extraction (FSPE) and could be reused without a significant loss of the catalytic activity and enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2008.07.125

Tetrahedron Letters 49 (2008) 5813–5815
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalytic enantioselective cyclopropanation of allylic alcohols
using recyclable fluorous disulfonamide ligand
*
Tsuyoshi Miura, Keisuke Itoh, Yumi Yasaku, Naka Koyata, Yasuoki Murakami, Nobuyuki Imai
Faculty of Pharmaceutical Sciences, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclopropanation of allylic alcohols with Et2Zn and CH2I2 in the presence of a catalytic amount of fluorous
disulfonamide 3 afforded the corresponding cyclopropylmethanols in 69–96% yield with 49–83% ee. The
fluorous ligand 3 was readily recovered from the reaction mixture by the fluorous solid-phase extraction
(FSPE) and could be reused without a significant loss of the catalytic activity and enantioselectivity.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 24 June 2008
Revised 19 July 2008
Accepted 23 July 2008
Available online 26 July 2008
The authors dedicate this article to the 80th
birthday of Professor E. J. Corey at Harvard
University.
Development of a catalytic enantioselective cyclopropanation is
an attractive research field because cyclopropane derivatives show
various kinds of bioactivities.1 Since Kobayashi developed the first
enantioselective Simmons–Smith cyclopropanation, some effective
methods have been reported.2 We have also reported enantioselec-
tive Simmons–Smith cyclopropanation catalyzed by chiral disulf-
R1
MsHN NHR2
1: R1 = H, R2 = SO2C6H4-p-NO2
2: R1 = H, R2 = Ts
onamides (1 and 2) derived from L-phenylalanine, which afforded
3: R1 = OCH2CH2CH2C8F17, R2 = Ts
the corresponding cyclopropylmethanols in 82–100% yield with
39–86% ee.3 However, recovery and reuse of the expensive chiral
ligands are generally difficult. The separation of the expensive
ligand from the product after cyclopropanation reaction and its
recycling are highly desirable. Furthermore, fluorous recovering
technique has been developed initially in the field of catalytic
chemistry by Horváth and Rabái,4 and Curran has elaborated the
fluorous solid-phase extraction (FSPE) methodology using fluorous
silica gel.5 Recently, asymmetric reactions by FSPE concept for
recovery and reuse of the expensive chiral ligands have been
reported.6
To recover and reuse the valuable ligands such as 1 and 2 for
enantioselective Simons–Smith cyclopropanation, we have attem-
pted the development of a novel chiral ligand with fluorous tag and
designed the fluorous disulfonamide 3. We guess that a fluorous
chain should be introduced into a distant position from the two
sulfonamides, which are important for the enantioselectivity.3c In
this Letter, we describe a catalytic enantioselective cyclopropana-
tion using flurous disulfonamide 3, which can be recovered and
reused.
was protected by t-butoxycarbonyl (Boc) group to give the corres-
ponding alcohol 5 in 98% yield. The reaction of 5 with the fluorous
tosylate 67 in the presence of potassium carbonate in acetonitrile
provided the fluorous alcohol 7 in 87% yield. The Boc group of 7
was removed by treatment with hydrogen chloride in ethyl ace-
tate, followed by the reaction with methanesufonyl chloride (MsCl)
in tetrahydrofuran (THF) to afford 78% yield of the corresponding
mesylate 8 in two steps. The azide 9 was obtained in 88% yield
by the reaction of 8 with sodium azide in N,N-dimethylformamide
(DMF). The azide 9 was hydrogenated on Pd/C in 1,4-dioxane, fol-
lowed by the reaction of p-toluenesulfonyl chloride (TsCl) in pyri-
dine to provide 93% yield of the desired fluorous disulfonamide 38
in two steps. We optimized the reaction conditions for enantiose-
lective cyclopropanation as shown in Table 1. The various reaction
temperatures from ꢀ23 °C to 10 °C were examined in the presence
of the fluorous disulfonamide 3 (0.1 equiv) in anhydrous dichloro-
methane (entries 1–6). The more suitable reaction temperature
was 0 °C as indicated in entry 4. The cyclopropanation was carried
out with 0.2 and 0.3 equiv of the fluorous disulfonamide 3 to afford
78% and 79% ee, respectively (entries 7 and 8).
The fluorous disulfonamide 3 was prepared as a novel recycl-
able chiral ligand (see Scheme 1). The amino group of tyrosinol 4
Next, the results of enantioselective cyclopropanation of various
allylic alcohols 10a–j in the presence of 0.2 equiv of 3 are shown in
Table 2.9 We selected methoxy and methyl substituents as repre-
sentative electron-donating groups (entries 2 and 3, respectively),
* Corresponding author. Tel./fax: +81 479 30 4610.
E-mail address: nimai@cis.ac.jp (N. Imai).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.125

5814
T. Miura et al. / Tetrahedron Letters 49 (2008) 5813–5815
p
-HO-Ph
H2N OH
p
-HO-Ph
BocHN OH
p-RfO-Ph
BocHN OH
6
(Boc)2O, NaOH
Rf-O-Ts ( )
1) HCl in AcOEt
in 1,4-dioxane
rt, 5 h
K2CO3 in MeCN
70 oC, 23 h
87%
2) MsCl, Et3N,
in THF, rt, 17 h
4
5
7
98%
78% (2 steps)
Rf = F17C8CH2CH2CH2-
p-RfO-Ph
p-RfO-Ph
p-RfO-Ph
1) H2, Pd-C in 1,4-dioxane
NaN3
2) TsCl in pyridine, rt, 3 h
93% (2 steps)
in DMF
MsHN OMs
8
MsHN N3
9
MsHN NHTs
80 oC, 3 h
3
88%
Scheme 1. Preparation of fluorous disulfonamide 3.
Table 2
Table 1
Cyclopropanation of various allylic alcohols 10a–j in the presence of 3a
Optimaization of reaction conditionsa
p
-RfO-Ph
MsHN NHTs
-RfO-Ph
p
3
3
R3
OH
10
R3
OH
11
*
MsHN NHTs
Ph
OH
10a
Ph
OH
11a
Et2Zn, CH2I2 in CH2Cl2
0 oC, 3 h
R4
R4
Et2Zn, CH2I2 in CH2Cl2
Rf = F17C8CH2CH2CH2-
Rf = F17C8CH2CH2CH2-
Entry Temperature (°C) Compound 3 (equiv) Time (h) Yield (%) ee (%)b
Entry
Compound 10
R3
R4
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
ꢀ23
ꢀ10
ꢀ5
0
5
10
0
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.3
23
3
3
88
95
95
97
97
95
93
97
63
69
68
74
66
66
78
79
1
2
3
4
5
6
7
8
9
10a
10b
10c
10d
10e
10f
10g
10h
10i
Ph
H
93
94
96
90
89
95
95
91
69
88
78b
77b
70b
83c
72c
74b
67d
70b
49b
71b
4-MeOC6H4
4-MeC6H4
4-CF3C6H4
4-ClC6H4
PhMe2Si
PhCH2CH2
TrOCH2
H
H
H
H
H
H
H
H
2.5
2.5
2.5
2.5
2.5
0
a
All reactions were carried out with 1 equiv of cinnamyl alcohol 10a, 2 equiv of
Et2Zn, and 3 equiv of CH2I2 in anhydrous CH2Cl2.
TrOCH2
Ph
10
10j
Ph
b
Determined by HPLC analysis using Chiralcel OD.
a
All reactions were carried out with 1 equiv of allylic alcohol 10, 0.2 equiv of 3,
2 equiv of Et2Zn, and 3 equiv of CH2I2 in anhydrous CH2Cl2.
b
Determined byHPLC analysis using Chiralcel OD.
Determined by HPLC analysis using Chiralcel AD after acetylation.
Determined by HPLC analysis using Chiralcel AD.
c
then trifluoromethyl and chloro substituents as electron-with-
drawing groups (entries 4 and 5, respectively) on the benzene ring.
The reaction of 10d substituted trifluoromethyl group afforded
higher enantioselectivity (83% ee) than those of other allylic alco-
hols 10a–c, and 10e (see entries 1–5). The other trans-oriented
allylic alcohols 10f–h were converted to the corresponding deriva-
tives in excellent yields with 67–74% ee. A low enantioselectivity
(49% ee) was obtained in the reaction of the cis-oriented allylic
alcohol 10i (entry 9). The reaction of 3,3-diphenyl-2-propen-1-ol
10j afforded 71% ee.
The fluorous ligand makes it possible to recover itself using flu-
orous silica gel based on solid-phase extraction. The fluorous
disulfonamide 3 was cleanly recovered (>92%) from the reaction
mixture by FSPE and the ligand 3 can be reused repeatedly. The
recovered and reused ligand 3 without further purification retains
a similar catalytic activity and enantioselectivity at least for two
times of the cyclopropanation as indicated in Table 3.
In summary, a novel fluorous disulfonamide 3 efficiently works
as a ligand in the Simmons–Smith reaction of various allylic alco-
hols to give the corresponding cyclopropane derivatives with good
enantioselectivities. It was observed that the enantioselectivities of
the reaction of allylic alcohols with the ligand 3 were nearly equal
to those with the original ligands (1 and 2).3 The ligand 3 with the
fluorous tag was readily recovered only by simple solid-phase
extraction using fluorous silica gel after reaction, and can be reused
without further purification. The catalytic activity and enantio-
d
Table 3
Recycling and reuse of the fluorous ligand 3 by FSPE methodologya
p-RfO-Ph
3
MsHN NHTs
Ph
OH
10a
Ph
OH
11a
Et2Zn, CH2I2 in CH2Cl2
0 oC, 3 h
Entry
Yield (%)
ee (%)b
Initial
1st reuse
2nd reuse
93
93
94
78
78
77
a
All reactions were carried out with 1 equiv of allylic alcohol 10a, the recovered
3 (ca. 0.2 equiv), 2 equiv of Et2Zn, and 3 equiv of CH2I2 in anhydrous CH2Cl2 at the
1st and 2 nd reuses.
b
Determined by HPLC analysis using Chiralcel OD.
selectivity of 3 used repeatedly are not reduced. Further applica-
tion to the synthesis of bioactive compounds and novel reactions
is now in progress.

T. Miura et al. / Tetrahedron Letters 49 (2008) 5813–5815
5815
5. (a) Curran, D. P. Synlett 2001, 1488–1496; (b) Curran, D. P. In The Handbook of
Fluorous Chemistry; Gladysz, J. A., Horváth, I. T., Curran, D. P., Eds.; Wiley-VCH:
Weinheim, 2004; pp 128–156.
6. For recent catalytic enantioselective reactions using fluorous ligands: (a) Zu, L.;
Xie, H.; Li, H.; Wang, J.; Wang, W. Org. Lett. 2008, 10, 1211–1214; (b) Chu, Q.; Yu,
M. S.; Curran, D. P. Org. Lett. 2008, 10, 749–752; (c) Cui, H.; Li, Y.; Zheng, C.; Zhao,
G.; Zhu, S. J. Fluorine Chem. 2008, 129, 45–50; (d) Horn, J.; Bannwarth, W. Eur. J.
Acknowledgements
This work was supported in part by Ajinomoto Award in Syn-
thetic Organic Chemistry, Japan, and by Grants-in-Aid for Scientific
Research (C) (No. 18590014) from the Japan Society for the Promo-
tion of Science. This work was performed through the Scientific
Research Project by CIS (Chiba Institute of Science).
ˇ
ˇ
´
Org. Chem. 2007, 2058–2063; (e) Malkov, A. V.; Figlus, M.; Stoncius, S.; Kocovsky,
P. J. Org. Chem. 2007, 72, 1315–1325.
7. Campo, F. D.; Lastécouères, D.; Vincent, J.-M.; Verlhac, J.-B. J. Org. Chem. 1999, 64,
4969–4971.
8. Fluorous disulfonamide 3: Colorless amorphous solid; ½a D20
ꢀ16.6 (c 1.00, CHCl3);
ꢁ
References and notes
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(m, 1H), 3.60 (m, 1H), 3.98 (t, J = 5.9 Hz, 2H), 5.22 (d, J = 8.4 Hz, 1H), 5.70 (t,
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9. A typical procedure of the cyclopropanation using 3 and 10a is as follows: To a
colorless solution of 10a (67.0 mg, 0.500 mmol) and the fluorous disulfonamide
3 (85.9 mg, 0.100 mmol) in 7.5 mL of dry dichloromethane were added dropwise
1.00 mL (1.00 mmol) of a 1.00 M solution of Et2Zn in hexane and CH2I2 (121 lL,
1.50 mmol) at ꢀ40 °C under an argon atmosphere. The reaction mixture was
stirred at 0 °C for 2.5 h, and quenched with 0.3 mL of triethylamine. The reaction
mixture was extracted three times with ethyl acetate. The organic layers were
combined, washed with brine, dried over anhydrous magnesium sulfate, and
evaporated. The residue was chromatographed on fluorous silica gel with 70%
methanol to afford 71.0 mg of a crude product. Then, the fluorous silica gel was
eluted with a 1:1 mixture of methanol and ethyl acetate, and the fraction was
evaporated to recover the fluorous ligand 3 (81.7 mg, 95%). The crude product
was purified by column chromatography on silica gel with a 2:1 mixture of
hexane and ethyl acetate to afford the pure 11a (68.9 mg, 93%) as a colorless oil.
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