A practical and controllable enantioselective synthesis of 2-phenyl-1-cyclopropanecarboxylates via a camphor-derived sulfonium ylide

Article abstract of DOI:10.1055/s-2005-869852

We have developed a practical and controllable enantioselective synthesis of 2-phenyl-1-cyclopropane-carboxylates via camphor-derived sulfonium ylide. The procedure has many advantages such as cheap starting materials, facile synthetic procedures, good yields, excellent diastereoselectivities and high enantioselectivities. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869852

LETTER
1621
A Practical and Controllable Enantioselective Synthesis of 2-Phenyl-1-
cyclopropanecarboxylates via a Camphor-Derived Sulfonium Ylide
A
P
ractica
l
and
C
o
u
ntrollable En
n
a
ntioselective Syn
H
thesis of Cyclopro
u
panecarboxy
a
lates ng, Zhi-Zhen Huang*
School of Chemisty and Chemical Engineering, Nanjing University, Nanjing 210093, P. R. China
Fax +86(25)83686240; E-mail: huangzhizhen0226@163.com
Received 30 March 2005
Initially, we employed camphor-derived sulfide 3 in a re-
action with ethyl bromoacetate (Scheme 1) and obtained
sulfonium salt 44 in 89% yield. Treatment of salt 4 with
sodium hydroxide gave stabilized sulfonium ylide 54 in
Abstract: We have developed a practical and controllable enantio-
selective synthesis of 2-phenyl-1-cyclopropane-carboxylates via
camphor-derived sulfonium ylide. The procedure has many advan-
tages such as cheap starting materials, facile synthetic procedures,
good yields, excellent diastereoselectivities and high enantioselec- about 90% yield. We tried to obtain pure ylide 5, however,
tivities.
this failed because the so called ‘stabilized ylide’ 5 was
found to gradually decompose. However, we were
pleased to find that, in the presence of potassium tert-but-
oxide, the reaction of sulfonium salt 4 with a, b-unsatur-
ated compound 6 in one-pot proceeded smoothly in an
ice-bath, affording trans-2-substituted-1-cyclopropane-
carboxylate 7a,b stereoselectively in good yield
(Scheme 2). This is the first example of a cyclopropana-
tion via camphor-derived stabilized sulfonium ylide. Al-
though the trans/cis ratio was high, the ee value for the
trans-isomers was rather low.
Key words: enantioselective synthesis, practical method, cyclopro-
panecarboxylate, sulfonium ylide, diastereoselectivity
Optically active 2-substituted-1-cyclopropanecarboxy-
lates, especially 2-phenyl-1-cyclopropanecarboxylates
are very useful intermediates in the synthesis of chiral
compounds and are present in many biologically impor-
tant substances.1 Recently the cyclopropanation via chiral
ylides has become one of the most common methods for
the enantioselective synthesis of cyclopropane deriva-
tives.2 However, only one report2b appeared in the litera-
ture on the enantioselective synthesis of 2-substituted-1-
cyclopropanecarboxylates via ylides. In this protocol,
chiral sulfide 1 is prepared in a poor 30% yield from
expensive (R)-pulegone. The reaction of sulfide 1 with
aliphatic bromide does not occur unless expensive silver
tetrafluoroborate is employed. Although excellent
enantioselectivities are achieved, one serious limitation is
that only one configuration of 2-aryl-1-cyclopropane-
carboxylate is obtained.3 Another serious limitation for its
practical application, especially on a large scale, is that an
expensive phosphazene base [EtN=P(NMe2)2N=
P(NMe2)3] is used to form the sulfonium ylides.3 Very
recently it was reported that chiral vinylcyclopropanes
can be synthesized by camphor-derived sulfonium ylide 2
Me
SMe
OH
BrCH2COOEt
SHCH2COHOEt
Br
OH
acetone
89%
4
3
Me
S
CHCOOEt
OH
5
t-BuOK, THF
0 °C
4
+
R
R
EtOOC
6
7
7a: R = COPh, Yield = 81%, trans:cis = 99:1, ee = 20%
7b: R = CO2CH2Ph, Yield = 76%, trans:cis = 99:1, ee = 24%
with excellent diastereoselectivity and enantioselectivi- Scheme 1 Asymmetric cyclopropanation reaction via camphor-
ty.2c Herein, we wish to report a practical and controllable
derived stabilized sulfonium ylide 5.
enantioselective synthesis of 2-phenyl-1-cyclopropane-
carboxylate via a camphor-derived sulfonium ylide.
We then tried to employ camphor-derived semi-stabilized
sulfonium ylide 9. This underwent reaction with a range
of a,b-unsaturated esters and resulted in the enantioselec-
tive synthesis of 2-phenyl-1-cyclopropanecarboxylate 7
(Scheme 2). It was found that the reaction of sulfide 3
with benzyl bromide afforded camphor-derived sulfo-
nium salt 84 in good yield at 0 °C. Further experiments
showed that in the presence of potassium tert-butoxide,
sulfonium salt 8 reacted smoothly with various a,b-un-
saturated esters or propenenitrile to give 2-phenyl-1-
cyclopropanecarboxylates 7c–f or 2-phenyl-1-cyclopro-
panenitrile 7g in good yields (Table 1).5 No epoxides were
observed in this cyclopropanation reaction. Excellent
Me
SH CHCH=CHTMS
OH
S
O
1
2
Figure 1
SYNLETT 2005, No. 10, pp 1621–1623
1
7
.0
6
.2
0
0
5
Advanced online publication: 07.06.2005
DOI: 10.1055/s-2005-869852; Art ID: U09205ST
© Georg Thieme Verlag Stuttgart · New York

1622
K. Huang, Z.-Z. Huang
LETTER
diastereoselectivities were achieved with the trans-isomer tuned at will just by changing the base. When sodium hy-
dominant in all cases. The experimental results also indi- dride was used instead of potassium tert-butoxide,
cated that (1R,2R)-2-phenyl-1-cyclopropanecarboxylates (1S,2S)-2-phenyl-1-cyclopropanecarboxylates 7c–f were
7c–f or (1R,2R)-2-phenyl-1-cyclopropanenitrile 7g could obtained with good opposite enantioselectivities
be obtained with excellent enantioselectivities when po- (Scheme 3). The absolute configuration of 7c–f was as-
tassium tert-butoxide was used as the base (Table 1, en- signed through the comparison of the sign of their optical
tries 1–7).
rotations with that of the known compounds. The (1R,2R)-
isomers of the known compounds 7c–g are levorotatory in
ethanol whereas (1S,2S)-isomers of the known com-
pounds 7c–f are dextrorotatory.7 It is noteworthy that
chiral sulfide 3 could be recovered almost quantitatively
and reused conveniently.
Interestingly, the enantioselectivity in the asymmetric
synthesis of 2-phenyl-1-cyclopropanecarboxylate can be
Me
SMe
OH
SCH2Ph
Br
PhCH2Br
OH
acetone
92%
NaH
H
COOR
8
+
COOR
8
3
S
S
THF
Me
S
Ph
H
CHPh
7c–f
7d: R = Et,
7e: R = n-Bu, 7f: R = PhCH2
OH
7c: R = Me,
9
Scheme 3 Highly stereoselective synthesis of trans-(2S,3S)-2-sub-
stituted-1-cyclopropanecarboxylates 7c–f via camphor-derived sul-
fonium ylide 9
t-BuOK
THF
Ph
H
8
+
COOR
R
R
COOR
H
7c–f
In conclusion, we have developed an efficient method for
the enantioselective synthesis of trans-(2R,3R)-2-phenyl-
1-cyclopropanecarboxylates with excellent enantioselec-
tivities and diastereoselectivities. Either enantiomer can
be obtained, at will just by changing the base, with good
to excellent enantioselectivities. The cheap starting mate-
rials, the facile preparation of chiral sulfonium ylide, ex-
cellent diastereoselectivities, and high enantioselectivities
make this synthetic method practical for organic synthesis
as well as having possible industrial applications.
7c: R = Me,
7d: R = Et,
7e: R = n-Bu, 7f: R = PhCH2
t-BuOK
THF
Ph
H
8
+
CN
R
R
CN
H
7g
Scheme 2 Highly stereoselective synthesis of trans-(2R,3R)-2-phe-
nyl-1-cyclopropanecarboxylates 7c–f or cyclopropanenitrile 7g via
camphor-derived sulfonium ylide 9.
Table 1 Controllable Enantioselective Synthesis of 2-Phenyl-1-cyclopropanecarboxylates 7 via Camphor-Derived Sulfonium Ylide 9
Entry COOR
Base
Temp (°C)
–50
Time (h)
12
Yield (%)a,b
trans/cisc
99:1
ee (%)d
91
Configuration
1
2
COOEt
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
NaH
84
87
82
88
91
79
75
76
71
80
76
R,R
R,R
R,R
R,R
R,R
R,R
R,R
S,S
COOEt
–10
12
97:3
90
3
COOMe
COOMe
COOn-Bu
COOCH2Ph
CN
–50
12
100:0
100:0
99:1
93
4
–10
12
90
5
–50
12
91
6
–50
12
98:2
95
7
–10
24
100:0
99:1
91
8
COOEt
–10
24
80
9
COOMe
COOn-Bu
COOCH2Ph
NaH
–10
24
98:2
85
S,S
10
11
NaH
–10
24
100:0
98:2
72
S,S
NaH
–10
24
82
S,S
a Isolated yields.
b All products are known compounds6 and were confirmed by 1H NMR, IR and mass spectroscopy.
c Determined by 1H NMR spectroscopy or GC.
d Determined by chiral HPLC on a Chiralcel OD-H column.
Synlett 2005, No. 10, 1621–1623 © Thieme Stuttgart · New York

LETTER
A Practical and Controllable Enantioselective Synthesis of Cyclopropanecarboxylates
1623
2.96 (s, 1 H), 2.82 (s, 3 H), 1.85–1.81 (m, 3 H), 1.56–1.48
(m, 2 H), 1.26 (t, J = 7.0 Hz, 3 H), 1.21 (s, 3 H), 0.97 (s, 3
H), 0.84 (s, 3 H). 8: Mp 107–109 °C. 1H NMR: d = 7.60 –
7.27 (m, 5 H), 6.21 (d, J = 7.4 Hz, 1 H), 5.71 (d, J = 12.0 Hz,
1 H), 5.51 (d, J = 12.0 Hz, 1 H), 4.54 (d, J = 7.4 Hz, 1 H),
4.11 (t, J = 7.4 Hz, 1 H), 2.86 (s, 3 H), 1.97 (d, J = 4.5 Hz, 1
H), 1.84–1.80 (m, 1 H), 1.66 (s, 1 H), 1.46–1.29 (m, 2 H),
1.15 (s, 3 H), 0.95 (s, 3 H), 0.81 (s, 3 H). MS (ESI): m/z =
291.1 (M – Br).
Acknowledgment
We thank the National Natural Science Foundation of China for its
financial support of the project 20332050.
References
(1) (a) Li, Z. N.; Liu, G. S.; Zheng, Z.; Chen, H. Tetrahedron
2000, 56, 7187. (b) Högberg, M.; Sahlberg, C.; Engelhardt,
P.; Norèen, R.; Kangasmetsä, J.; Johansson, N. G.; Öberg,
B.; Vrang, L.; Zhang, H.; Sahlberg, B. L.; Unge, T.;
LÖvgren, S.; Fridborg, K.; Bäckbro, K. J. Med. Chem. 1999,
42, 4150. (c) Ikeda, T.; Kawai, A.; Mano, T.; Okumura, Y.;
Stevens, R. W. Japanese Patent 90/323 814 27, 1990.
(d) Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B.
Chem. Rev. 2003, 103, 971.
(2) (a) Li, A. H.; Dai, L. X.; Aggarwal, V. K. Chem. Rev. 1997,
97, 2341. (b) Solladié-Cavallo, A.; Diep-Vohuule, A.;
Isarno, T. Angew. Chem. Int. Ed. 1998, 37, 1689. (c) Ye, S.;
Huang, Z. Z.; Xia, C. A.; Tang, Y.; Dai, L. X. J. Am. Chem.
Soc. 2002, 124, 2432.
(5) General procedure for the controllable enantioselective
synthesis of 2-phenyl-1-cyclopropanecarboxylates 7c–f via
camphor-derived sulfonium ylide 9: To a stirred suspension
of sulfonium salt 8 (445 mg, 1.2 mmol) and a,b-unsaturated
ester (1.0 mmol) in THF (6 mL) was added t-BuOK (336 mg,
3.0 mmol) or NaH (72 mg, 3.0 mmol) in one portion at the
desired temperature (Table 1). After stirring for the time
indicated (Table 1), the reaction mixture was passed through
a short silica gel column, which was eluted with ethyl
acetate. After concentration of the eluent, the residue was
purified by flash column chromatography or preparative
TLC, giving 2-phenyl-1-cyclopropanecarboxylate 7c–f.
(6) (a) Johnson, C. R.; Rogers, P. E. J. Org. Chem. 1973, 38,
1793. (b) Charett, A. B.; Janes, M. K.; Lebel, H.
(3) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37,
611.
(4) 4: Mp 103–105 °C. 1H NMR: d = 5.77 (s, 1 H), 5.57 (d,
J = 16.6 Hz, 1 H), 5.39 (d, J = 16.6 Hz, 1 H), 5.22 (d, J = 7.1
Hz, 1 H), 4.33 (q, J = 7.0 Hz, 2 H), 4.25 (m, 1 H), 3.19 (s, 3
H), 2.04 (d, J = 4.5 Hz, 1 H), 2.03–1.87 (m, 2 H), 1.56–1.50
(m, 2 H), 1.35 (t, J = 7.1 Hz, 3 H), 1.23 (s, 3 H), 1.01 (s, 3
H), 0.87 (s, 3 H). MS (ESI): m/z = 287.1 (M – Br). 5: 4.16–
4.14 (m, 1 H), 4.15–3.90 (m, 3 H), 3.85 (d, J = 7.2 Hz, 1 H),
Tetrahedron: Asymmetry 2003, 14, 867. (c) Li, Z. N.;
Zheng, Z.; Chen, H. L. Tetrahedron: Asymmetry 2000, 11,
1157. (d) Doyle, M. P.; Dorow, R. L.; Tamblyn, W. H. J.
Org. Chem. 1982, 47, 4095.
(7) (a) Inouye, Y.; Sugita, T.; Walborsky, H. M. Tetrahedron
1964, 20, 1695. (b) Evans, D. A.; Woerpel, K. A.; Scott, M.
J. Angew. Chem. Int. Ed. 1992, 31, 430.
Synlett 2005, No. 10, 1621–1623 © Thieme Stuttgart · New York