Syntheses of (R)-(+)-cibenzoline and analogues via catalytic enantioselective cyclopropanation using (S)-phenylalanine-derived disulfonamide

Article abstract of DOI:10.1016/j.tetasy.2006.11.027

Cyclopropanation of 3,3-diaryl-2-propen-1-ols 1 with Et₂Zn and CH₂I₂ proceeded in the presence of a catalytic amount of (S)-2-(methanesulfonyl)amino-1-(p-toluenesulfonyl)amino-3-phenylpropane 2 to afford the corresponding

Full text of DOI:10.1016/j.tetasy.2006.11.027

Tetrahedron: Asymmetry 17 (2006) 3067–3069
Syntheses of (R)-(+)-cibenzoline and analogues via
catalytic enantioselective cyclopropanation using
(S)-phenylalanine-derived disulfonamide
Tsuyoshi Miura, Yasuoki Murakami and Nobuyuki Imai*
Faculty of Pharmaceutical Sciences, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan
Received 25 October 2006; accepted 15 November 2006
Available online 12 December 2006
Abstract—Cyclopropanation of 3,3-diaryl-2-propen-1-ols 1 with Et2Zn and CH2I2 proceeded in the presence of a catalytic amount of
(S)-2-(methanesulfonyl)amino-1-(p-toluenesulfonyl)amino-3-phenylpropane 2 to afford the corresponding cyclopropylmethanols with
20–76% ee. (+)-2,2-Diphenylcyclopropylmethanol 3a (76% ee) was oxidized with IBX in DMSO, followed by NaClO2, H2O2, and
NaH2PO4 in MeCN–H2O to give the corresponding acid 5a, which was converted with ethylenediamine, in the presence of PyBOP
and Et3N in CH2Cl2, to the amide 6a in quantitative overall yield from 3a. Amide 6a was cyclized at 160 °C under reduced pressure
(2 mmHg) to afford (R)-(+)-cibenzoline in 55% yield.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Cibenzoline is a commercially available medicine as a class
I antiarrhythmic agent1 and consists of four rings, such as a
cyclopropane skeleton which has a stereogenic carbon, two
benzene ones, and an imidazoline one. Since Kobayashi re-
ported the first and unique enantioselective Simmons–
Smith cyclopropanation catalyzed by a C2-symmetrical
disulfonamide–zinc or aluminum complex,2e,h–j Denmark
has optimized conditions for Kobayashi’s method.2d,f,g Re-
cently, Charette has developed another enantioselective
catalytic cyclopropanation using 25 mol % of C2-symmetri-
cal titanium complex of (4R,5R)-2,2-diethyl-a,a,a0,a0-tetra-
In a preliminary investigation, the reaction of 3,3-diphenyl-
2-propen-1-ol 1a with Et2Zn and CH2I2 in the presence of
10 mol % of 2 afforded the corresponding cyclopropane
product 3a5 with 76% ee, as indicated in entry 1 of Table
1. The cyclopropanation of 3,3-diaryl-2-propen-1-ols
substituted on the aromatic ring by electron-donating or
electron-withdrawing groups was then examined: the re-
sults from the cyclopropanation of various 3,3-diaryl-2-
propen-1-ols 1b–1f with Et2Zn and CH2I2 in the presence
of 10 mol % of 2 are collected in Table 1. We selected meth-
oxy and methyl substituents as representative electron-
donating groups (see entries 2 and 3), trifluoromethyl and
chloro substituents as electron-withdrawing groups (see en-
tries 4 and 5), and a fluorenyl substituent for making the
spiro-ring (see entry 6). Fortunately, cyclopropanation of
un-substituted allylic alcohol 1a, which can be converted
to cibenzoline gave the highest ee among these 3,3-diaryl-
2-propen-1-ols 1a–1f. The reactions of the allylic alcohols
phenyl-1,3-dioxane-4,5-dimethanol
(Ti-TADDOLate),
which is a large and complex molecule.2c We have devel-
oped a catalytic enantioselective Simmons–Smith reac-
tion2a,b and alkylation3a using the simple disulfonamides
derived from a-amino acids. Herein, we report a catalytic
enantioselective cyclopropanation of 3,3-diaryl-2-propen-
1-ols 14 with Et2Zn and CH2I2 using 10 mol % of (S)-2-
(methanesulfonyl)amino-1-(p-toluenesulfonyl)amino-3-phen-
ylpropane 2 and synthesis of optically active cibenzoline
and some analogues.
Ph
MsHN
NHTs
Ar
OH
*
Ar
OH
2
Ar
Ar
Et2Zn, CH2I2 in CH2Cl2
at 0 oC for 24 h
*
Corresponding author. Tel./fax: +81 479 30 4610; e-mail: nimai@
cis.ac.jp
3
1
(20~76% ee)
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.027

3068
T. Miura et al. / Tetrahedron: Asymmetry 17 (2006) 3067–3069
Table 1. Cyclopropanation of 3,3-diaryl-2-propen-1-ols 1a–f in the presence of 2a
25
Entry
1
Ar
Yield (%)
eeb (%)
Eluentc (%)
½aꢀD
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
82
40
71
84
32
54
76
48
67
20
29
51
5
5
5
5
5
5
+115.9 (c 1.07, CHCl3)
+60.4 (c 1.41, CHCl3)
+95.4 (c 1.33, CHCl3)
+13.4 (c 1.29, CHCl3)
+30.6 (c 1.58, CHCl3)
+9.4 (c 1.41, CHCl3)
4-MeOC6H4
4-MeC6H4
4-CF3C6H4
4-ClC6H4
Fluorenyl
a All reactions were carried out with 1 equiv of 3,3-diaryl-2-propen-1-ol 1, 0.1 equiv of 2, 2 equiv of Et2Zn, and 3 equiv of CH2I2 in anhydrous CH2Cl2.
b Determined by HPLC analysis using Chiralcel OD.
c The number indicates concentration of i-PrOH in hexane as an eluent on HPLC analysis for determination of enantiomeric excess of the product.
1b and 1c (entries 2 and 3, respectively) substituted with an
electron-donating group afforded higher enantioselectivi-
ties than those of the allylic alcohols 1d and 1e (entries 4
and 5, respectively) substituted with an electron-withdraw-
ing group.
verted under reduced pressure (2 mmHg) at 160 °C for
37 h to (R)-(+)-cibenzoline7 in 55% yield, as shown in
Scheme 1. These results suggest that the absolute configu-
rations of compounds 3a–6a are (R). The fluorenyl alcohol
3f, which is connected at the ortho-position of each benzene
ring in 3a, was converted to the corresponding amide 6f in
quantitative overall yield in a similar manner to that
described for the preparation of 6a, Scheme 2. The amide
6f was not cyclized and recovered in 52% yield under
reduced pressure (2 mmHg) at 160 °C for 26 h. It was
found that the fluorenyl group of the amide 6f stereo-
chemically hinders the formation of the imidazoline ring
because the two benzene rings of 6f are fixed in the same
plane.
(R)-(+)-Cibenzoline was synthesized from (+)-2,2-diphen-
ylcyclopropylmethanol 3a as follows. Alcohol 3a was
oxidized with 2-iodoxybenzoic acid (IBX) in dimethylsulf-
oxide (DMSO) at rt for 3 h to afford the corresponding
aldehyde 4a, which was treated with NaClO2, H2O2, and
NaH2PO4 in MeCN–H2O at rt for 30 min to give acid
5a. Acid 5a was condensed with ethylenediamine in the
presence of benzotriazol-1-yloxytripyrrolidinophospho-
nium hexafluorophosphate (PyBOP) and Et3N in CH2Cl2
at rt for 5 h to obtain the corresponding amide 6a6 in quan-
titative overall yield from 3a. Then, amide 6a was con-
Cyclopropanemethanols 3c, 3d, 3e which are substituted
with methyl, trifluoromethyl, chloro groups at the para-po-
O
OH
I
O
(IBX)
O
NaClO2, H2O2
Ph
NaH2PO4 in MeCN-H2O
Ph
OH
Ph
CHO
CO2H
in DMSO
Ph
Ph
Ph
3a
4a
5a
at rt for 30 min
at rt for 3 h
H
2 mmHg
H2NCH2CH2NH2
N
Ph
Ph
CONHCH2CH2NH2
at 160 oC for 37 h
in 55% yield
PyBOP, Et3N in CH2Cl2
at rt for 5 h
Ph
(R)-(+)-cibenzoline
N
Ph
6a
in quantitative yield form 3a
Scheme 1. Synthesis of (R)-(+)-cibenzoline from (+)-2,2-diphenylcyclopropylmethanol 3a.
OH
*
*
NaClO2, H2O2
IBX
CHO
NaH2PO4 in MeCN-H2O
at rt for 3 h
in DMSO
3f
4f
at rt for 2.5 h
*
*
CONHCH2CH2NH2
H2NCH2CH2NH2
CO2H
PyBOP, Et3N in CH2Cl2
at rt for 3 h
6f
5f
in quantitative yield form 3f
Scheme 2. Trial for the preparation of a cibenzoline analogue from (+)-cyclopropylmethanol 3f.

T. Miura et al. / Tetrahedron: Asymmetry 17 (2006) 3067–3069
3069
Table 2. Synthesis of (R)-(+)-cibenzoline and the analogues from (+)-2,2-diarylcyclopropylmethanols 3a–3f
NaClO2, H2O2
IBX
Ar
OH
3a-3f
Ar
Ar
Ar
*
*
*
*
CHO
CO2H
NaH2PO4 in MeCN-H2O
at rt
in DMSO
at rt
Ar
Ar
Ar
Ar
4a-4f
5a-5f
H
N
H2NCH2CH2NH2
2 mmHg
at 160 oC
Ar
*
CONHCH2CH2NH2
PyBOP, Et3N in CH2Cl2
at rt
N
Ar
6a-6f
cibenzoline and analogues
Cibenzoline and the analogues
Entry
3
Ar
6
25
25
Yielda (%)
½aꢀD
Yield (%)
½aꢀD
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
Ph
Quant.
0
Quant.
89
55
Quant.
+102.8 (c 1.03, MeOH)
—
+23.9 (c 1.38, MeOH)
+19.2 (c 1.27, MeOH)
+38.7 (c 1.39, MeOH)
+97.4 (c 1.63, MeOH)
55
—
43
46
50
0
+30.1 (c 1.12, MeOH)
—
+25.6 (c 0.64, MeOH)
+21.6 (c 0.75, MeOH)
+3.3 (c 0.67, MeOH)
—
4-MeOC6H4
4-MeC6H4
4-CF3C6H4
4-ClC6H4
Fluorenyl
a Overall yields from the cyclopropylmethanols 3a–3f.
K.; Nokami, J. Tetrahedron Lett. 1997, 38, 1423–1426; For the
other catalytic enantioselective Simmons–Smith cyclopropa-
nation: (c) Charette, A. B.; Molinaro, C.; Brochu, C. J. Am.
Chem. Soc. 2001, 123, 12168–12175; (d) Denmark, S. E.;
O’Connor, S. P. J. Org. Chem. 1997, 62, 3390–3401; (e)
Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno, M.; Imai,
N.; Kobayashi, S. Tetrahedron 1995, 51, 12013–12026; (f)
Denmark, S. E.; Christensen, B. L.; Coe, D. M.; O’Connor, S.
P. Tetrahedron Lett. 1995, 36, 2215–2218; (g) Denmark, S. E.;
Christensen, B. L.; O’Connor, S. P. Tetrahedron Lett. 1995, 36,
2219–2222; (h) Imai, N.; Sakamoto, K.; Takahashi, H.;
Kobayashi, S. Tetrahedron Lett. 1994, 35, 7045–7048; (i) Imai,
N.; Takahashi, H.; Kobayashi, S. Chem. Lett. 1994, 177–180;
(j) Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S.
Tetrahedron Lett. 1992, 33, 2575–2578.
sition on the benzene rings were converted to the corre-
sponding cibenzoline analogues in similar methods to the
preparation of cibenzoline. All specific rotations of amide
6a–6f, cibenzoline, and cibenzoline analogues are summa-
rized in Table 2.
3. Conclusion
In summary, (S)-2-(methanesulfonyl)amino-1-(p-toluene-
sulfonyl)amino-3-phenylpropane 2 works efficiently as a
catalyst in the Simmons–Smith cyclopropanation of steri-
cally hindered allylic alcohols such as 3,3-diaryl-2-pro-
pen-1-ols 1a–1f. In our procedure, it is possible to
prepare various chiral 2,2-disubstituted cyclopropylmetha-
nols conveniently and to synthesize the corresponding
chiral cibenzoline analogues. We are still working on the
optimization of a-amino acid-derived chiral disulfona-
mides for the catalytic enantioselective cyclopropanation
of 3,3-diphenyl-2-propen-1-ol 1a.
3. (a) Imai, N.; Nokami, J.; Nomura, T.; Ninomiya, Y.; Sinobe,
A.; Matsushiro, S. The Bull. Okayama Univ. Sci. 2002, 38A,
47–52; For the other catalytic enantioselective alkylation with
Et2Zn in the presence of disulfonamide: (b) Takahashi, H.;
Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S.
Tetrahedron 1992, 48, 5691–5700; (c) Takahashi, H.; Kawa-
kita, T.; Yoshioka, M.; Ohno, M. Tetrahedron Lett. 1989, 30,
7095–7098; (d) Yoshioka, M.; Kawakita, T.; Ohno, M.
Tetrahedron Lett. 1989, 30, 1657–1660.
Acknowledgements
4. Imai, N.; Noguchi, T.; Nokami, J.; Otera, J. The Bull.
Okayama Univ. Sci. 2003, 39A, 47–55.
5. (a) Turnbull, M. D. J. Chem. Soc., Perkin Trans. 1 1997, 1241–
1247; (b) Watanabe, N.; Matsuda, H.; Kuribayashi, H.;
Hashimoto, S. Heterocycles 1996, 42, 537–542, and the
references cited therein.
This work was supported in part by Ajinomoto Award in
Synthetic Organic Chemistry, Japan and by Grants-in-
Aid for Scientific Research (C) (No. 18590014) from the
Japan Society for the Promotion of Science. This work
was performed through the Scientific Research Project by
CIS (Chiba Institute of Science).
6. Compound 6a: 1H NMR (CD3OD) d 1.50 (1H, dd, J = 5.0,
8.2 Hz), 2.16 (1H, dd, J = 5.0, 5.9 Hz), 2.53 (1H, dd, J = 5.9,
8.2 Hz), 2.73 (2H, m), 3.23 (2H, t, J = 6.2 Hz), 7.12–7.36 (10H,
m); 13C NMR (CD3OD) d 19.4, 31.0, 38.6, 40.2, 41.1, 127.5,
127.9, 128.7, 129.3, 129.4, 130.9, 142.0, 146.6, 173.6; HRMS
(ESI-TOF): Calcd for C18H21N2O (M+H+): 281.1648. Found:
281.1654.
References
7. (R)-(+)-Cibenzoline:1 1H NMR (CD3OD) d 1.58 (1H, dd,
J = 5.4, 8.6 Hz), 2.09 (1H, dd, J = 5.4, 6.3 Hz), 2.43 (1H, dd,
J = 6.3, 8.6 Hz), 3.20 (2H, m), 3.37 (2H, m), 7.11–7.38 (10H,
m); 13C NMR (CD3OD) d 19.5, 25.2, 30.8, 39.9, 48.9, 127.6,
128.1, 128.8, 129.3, 129.5, 131.0, 141.4, 146.4, 168.9; HRMS
(ESI-TOF): Calcd for C18H19N2 (M+H+): 263.1543. Found:
263.1540.
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Chirality 1989, 1, 223–234, and the references cited therein;
(b) Tilley, J. W.; Clader, J. W.; Wirkus, M.; Blount, J. F. J.
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2. (a) Imai, N.; Nomura, T.; Yamamoto, S.; Ninomiya, Y.;
Nokami, J. Tetrahedron: Asymmetry 2002, 13, 2433–2438; (b)
Imai, N.; Sakamoto, K.; Maeda, M.; Kouge, K.; Yoshizane,