Reagent-Controlled Asymmetric Iodolactonization Using Cinchona Alkaloids as Chiral Sources

Article abstract of DOI:10.1081/SCC-120028633

A novel method for reagent-controlled asymmetric iodolactonization of 5-aryl-4-pentenoic acids is reported. This work uses carboxylate ion pairs combined with cinchona alkaloids as chiral sources of carboxylate anion for the first time leading to a mixture of two regio-isomeric iodolactones with moderate enantioselectivity (exo-18.5% ee, endo-35.0% ee) under mild reaction conditions.

Full text of DOI:10.1081/SCC-120028633

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Reagent‐Controlled Asymmetric Iodolactonization
Using Cinchona Alkaloids as Chiral Sources
a
a
a
a
Mang Wang , Lian Xun Gao , Wei Yue & Wen Peng Mai
a
Lab 2, Changchun Institute of Applied Chemistry, Chinese Academy of Science,
Changchun, 130022, P.R. China
Published online: 21 Aug 2006.
To cite this article: Mang Wang , Lian Xun Gao , Wei Yue & Wen Peng Mai (2004) Reagent‐Controlled Asymmetric
Iodolactonization Using Cinchona Alkaloids as Chiral Sources, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 34:6, 1023-1032, DOI: 10.1081/SCC-120028633
To link to this article: http://dx.doi.org/10.1081/SCC-120028633
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 6, pp. 1023–1032, 2004
Reagent-Controlled Asymmetric
Iodolactonization Using Cinchona
Alkaloids as Chiral Sources
*
Mang Wang, Lian Xun Gao, Wei Yue, and Wen Peng Mai
Lab 2, Changchun Institute of Applied Chemistry, Chinese Academy of
Science, Changchun, P.R. China
ABSTRACT
A novel method for reagent-controlled asymmetric iodolactonization of
5
-aryl-4-pentenoic acids is reported. This work uses carboxylate ion pairs
combined with cinchona alkaloids as chiral sources of carboxylate anion
for the first time leading to a mixture of two regio-isomeric iodolactones
with moderate enantioselectivity (exo-18.5% ee, endo-35.0% ee) under
mild reaction conditions.
Halolactonization of unsaturated acids is a powerful process in synthetic
organic chemistry for regio- and stereoselective functionalization of double
[1]
bonds. Much recent work has centered on asymmetric halolactonization in
*
Correspondence: Lian Xun Gao, Lab 2, Changchun Institute of Applied Chemistry,
Chinese Academy of Science, Changchun, 130022, P.R. China; E-mail: lxgao@
ciac.jl.cn.
1
023
DOI: 10.1081/SCC-120028633
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
1
024
Wang et al.
which the one or two new stereo centers are generated and a high degree of
[2]
chiral induction can be achieved depending on the structure of the substrate.
Although this type of substrate-controlled asymmetric induction in this
cyclization was well described and applied in the synthesis of natural
[
3]
products, the investigation on reagent-controlled asymmetric halolactoniza-
tion remained poorly explored. To the best of our knowledge, there are only
four examples of reagent-controlled stereoselective halolactonization to
[
4,5]
date
and the stereochemistry of this lactonization reaction can be control-
[4]
[5]
led by chiral carboxylate anion and chiral positive halogen ion. In this
context, we have developed a new protocol for reagent-controlled asymmetric
iodolactonization using cinchona alkaloid-carboxylate ion pairs as chiral
sources of carboxylate anion. Here the new experimental results are reported.
As a probe, 5-phenyl-4-pentenoic acid 1a was treated with iodine and
saturated aqueous sodium hydrogen carbonate in CH Cl (Sch. 1). An
2
2
expected competition between the exo mode and the endo mode of cyclization
[
1a,1c,1d]
for the formation of lactone was observed.
d-lactone was obtained with the ratio of 20 : 80. The major product is the endo-
In fact, a mixture of g- and
2
1
product d-lactone 3a (IR 1723 cm ) due to the electronic factors from the
phenyl group at the 5-position of 1a. This product is not separable from the
mixture with its isomer g-lactone 2a (IR 1760 cm ) by chromatography in
our experiment. Interestingly, when cinchonidine 4a was introduced as alkali
instead of NaHCO , the yield ratio of the reaction products 2a : 3a was
2
1
3
reversed with detectable enantioselectivity. In this case, the endo-product 3a is
not dominant product perhaps resulting from the steric repulsion between the
phenyl group and the larger carboxylate ion pair combined with cinchonidine
when the carbon at the 5-position is being attacked by the carboxylate anion.
The above initial result prompted us to pursue the enantioselective iodolacton-
ization using cinchona alkaloids as chiral sources.
The solvent effect on the selectivity of this reaction was first investigated.
Among the solvent tested (Table 1), it was observed that methylene chloride
gave the relatively better stereoselectivity for the formation of lactone 2a and
3a. Another promising solvent was chloroform, leading to an ee of 8.0% for 2a
and 17.5% for 3a. Comparatively, when ether, tetrahydrofuran, acetonitrile or
Scheme 1.

ORDER
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Reagent-Controlled Asymmetric Iodolactonization
1025
Table 1. Effect of solvent on the stereoselectivity of iodolactonization of 1a using 4a
a
as alkali.
Reaction
time (h)
% Yields
b
2a þ 3a
% Recovery
4a
c
d
% ee 2a % ee 3a
d
Solvent
2a : 3a
Et
THF
2
O
96
45
70
95
16
18
80
83
92 : 8
5.5
2.5
7.0
9.0
8.0
8.0
15.0
4.5
3.5
0
84
87
99
80
87
86
83 : 17
85 : 15
92 : 8
CH
3
CN
e
6
89
80
C
CH Cl
6
H
100
90
68 : 32
75 : 25
21.5
17.5
2
2
CHCl3
a
1
a (1 mmol), 4a (1.1 mmol), I
Isolated yield.
2
(1.5 mmol), 08C.
b
c
1
Determined by HNMR.
d
1
Determined by HNMR with R-(2)-2,2,2-trifloro-1-(9-anthryl) ethanol. The absolute
configuration of major enantiomer was not determined.
e
At room temperature (about 158C).
benzene were selected as solvent, the iodolactonization need to suffer longer
reaction process with lower selectivity. Further optimization of the reaction
conditions was then examined by investigating temperature effects. It was
found that the temperature (2788C, 2208C, 08C and r.t.) had only limited
influence on the stereoselectivity of this cyclization. Since higher temperature,
such as 308C or higher, is disadvantageous to the stability of iodolactones, 08C
was chosen as the preferred reaction temperature for iodolactonization.
Several other commercially available cinchona alkaloids were investi-
gated as chiral alkali (Figure 1). From the results described in Table 2, it is
found that cinchonidine 4a and quinine 4d result in better selectivity than
others. Whereas, O-substituted alkaloids 4e and 4f do not lead to higher
selectivity. In all cases, recoveries of 4 are excellent. Compared with other
cinchona alkaloids, when 4b and 4c as chiral alkali, the iodolactonization
generated the reverse rotation in major enantiomer of products 2a and 3a. But
the absolute configurations of major enantiomer of 2a and 3a were not
determined.
Iodolactonization of a number of 5-substituted-4-pentenoic acids (5-
substituent-4-pentenoic acids 1a–1e and 1g were prepared stereoselectively
from 1-substituent-propylen-1-ol and triethyl orthoacetete via a Claisen
rearrangement followed by basic cleavage of the ethyl ester. About general
[6]
procedure for Claisen rearrangement, see: Ref. ) was then performed
successfully (Sch. 2) using 4a and 4d as chiral alkali in CH Cl at 08C and the
results are summarized in Table 3. Obviously, aromatic substituent at the
2
2

ORDER
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1
026
Wang et al.
Figure 1.
Table 2. Results of the steroselective iodolactonization of 1a using different 4 as
a
alkali.
Reaction
time (h)
% Yields
b
2a þ 3a
% Recovery
4
c
d
% ee 2a % ee 3a
d
Alkali 4
2a : 3a
4
4
4
4
4
4
a
b
c
d
e
f
16
18
22
22
36
24
100
93
68 : 32
75 : 25
84 : 16
76 : 24
66 : 34
82 : 18
8.0
6.0
2.5
9.5
8.5
7.0
21.5
16.0
16.0
28.0
3.0
87
90
82
82
98
93
96
100
83
80
3.5
a
1
2 2 2
a (1 mmol), 4 (1.1 mmol), CH Cl , I (1.5 mmol), 08C.
b
Isolated yield.
Determined by HNMR.
c
1
d
1
Determined by HNMR with R-(2)-2,2,2-trifloro-1-(9-anthryl) ethanol. The absolute
configuration of major enantiomer was not determined.

ORDER
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Reagent-Controlled Asymmetric Iodolactonization
1027
Scheme 2.
5-position of the acids 1 (1a–1e) is necessary to have the proper selectivity.
Unsaturated carboxylic acids (1f and 1g) with hydrogen or an aliphatic
substituent at the 5-position only lead to racemic g-lactones. Table 3 shows
that the substrate with strong electron-donating aryl at the 5-position leads to
an increase in the ratio of the endo-product to the exo-product during
cyclization (entries 4 and 11). Unfortunately, when an aryl with strong
electron-withdrawing substituent was introduced to form 5-aryl-4-pentenoic
acid, such as pyridinyl, no lactone was detected after five days under the
similar reaction conditions. Besides the recovery of the substrate, the reaction
a
Table 3. Substituted carboxylic acids 1 in iodolactonization reaction.
Acid Alkali Reaction % Yields
b
% Recovery
4
c
d
% ee 2 % ee 3
d
Entry
1
4
time (h)
2 þ 3
2 : 3
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
4a
4a
4a
4a
4a
4a
4a
4d
4d
4d
4d
4d
4d
4d
12
8
100
95
68 : 32
38 : 62
65 : 35
0 : 100
86 : 14
100 : 0
100 : 0
76 : 24
57 : 43
74 : 26
0 : 100
83 : 17
100 : 0
100 : 0
8.0
8.5
18.5
–
21.5
32.0
25.5
35.0
25.0
–
87
95
93
93
90
96
98
82
84
90
92
91
94
90
12
24
23
7
100
33
89
88
5.5
0
1g
1a
1b
1c
1d
1e
1f
8
86
0
–
22
14
16
47
30
10
12
100
93
9.5
10.0
15.0
–
28.0
32.0
31.5
32.0
34.0
–
10
11
12
13
14
95
25
86
90
11.5
0
1g
89
0
–
a
1
(1 mmol), 4 (1.1 mmol), CH Cl , I (1.5 mmol), 08C.
2
2
2
b
c
Isolated yield.
1
Determined by HNMR.
d
1
Determined by HNMR with R-(2)-2,2,2-trifloro-1-(9-anthryl) ethanol. The absolute
configuration of major enantiomer was not determined.

ORDER
REPRINTS
1
028
Wang et al.
1
resulted in complex mixtures which could not identified by H NMR. From the
results described in Table 3, it is clear that the ee values of 3 are higher than
those of their isomer 2 in all cases. It can be rationally explained that the aryl
substituent located at the 5-position can maximize the asymmetric face of the
endo-mode cyclization by the steric repulsion with the chiral carboxylate ion
pair formed with cinchona.
In conclusion, we have developed a new protocol for reagent-controlled
asymmetric iodolactonization. This method uses carboxylate ion pair
combined with commercially available cinchona alkaloids as chiral sources
of carboxylate anion for the first time leading to a mixture of iodolactonized
products with moderate enantioselectivity. Further studies to optimize this
reaction are in progress.
EXPERIMENTAL SECTION
IR spectra (KBr) were measured using a Bio-Rad FTS135 spectrometer.
1
The H NMR spectra were determined on Bruker spectrometer (300, 400 or
600 MHz) in CDCl with TMS as internal standard. Mass spectra were
3
recorded on LCQ spectrometer. Elemental analyses were obtained on a
VarioEL analyser. Unless otherwise noted materials were obtained from
commercially available sources and used without further purification.
General Procedure for Iodolactonization of Acids 1
To a solution of acid 1a–1g (1 mmol) in CH Cl (10 mL) was added 4a–
2
2
4f (1.1 mmol). After stirring for 10 min, iodine (1.5 mmol) was added to this
rapidly stirred reaction mixture at 08C. The flask was protected from light and
stirred for 7–47 h at 08C. The reaction mixture was diluted with CH Cl2
2
(
layer was separated and washed with saturated aqueous NaHCO3
100 mL) and then quenched with saturated aqueous Na S O . The organic
2 2 3
(
anhydrous MgSO , filtered, and evaporated to afford a mixture of two regio-
2 Â 60 mL), 2N HCl (2 Â 60 mL) and brine (1 Â 60 mL), dried over
4
isomeric products (25–100%). The reaction products need to be stored at
2
208C protected from light. The ratio of two isomers was determined by
HNMR. The enantiomeric excess was also confirmed by HNMR (600 MHz)
1
1
spectrum of a mixture of endo- and exo-lactones with R-(2)-2,2,2-trifloro-1-
(
9-anthryl)ethanol.
The aqueous acidic washes were made basic with NaOH and extracted
with CH Cl .The organic layer was dried over MgSO , filtered, and evapor-
4
2
2
ated to give recovered 4 (82–98%) as a white solid.

ORDER
REPRINTS
Reagent-Controlled Asymmetric Iodolactonization
1029
1
-(Iodo-phenyl-methyl)-dihydrofuran-2-one 2a. H NMR (400 MHz,
5
CDCl ): d ¼ 2.12–2.20 (m, 1H), 2.53–2.65 (m, 3H), 4.86–4.92 (m, 1H,
3
CHO), 5.12 (d, J ¼ 8.0 Hz, 1H, CHI), 7.27–7.34 (m, 3H), 7.41 (d, J ¼ 7.6 Hz,
2
1
2
H). IR (KBr): 3029, 2940, 1760, 1188 cm . MS (EI, 30 eV): m/z (%) 302
þ
(
4) [M ], 175 (100), 129 (20), 91 (75). Anal. Calcd. for C H IO : C 43.73 H
1
1
11
2
3.67, Found: C 43.47 H 3.56. Elemental analyses was obtained with a mixture
of two structural isomers 2a and 3a.
-Iodo-6-phenyl-tetrahydro-pyran-2-one 3a. H NMR (400 MHz,
1
5
CDCl ): d ¼ 2.30–2.49 (m, 2H), 2.68–2.76 (m, 1H), 2.82–2.90 (m, 1H),
3
4
.40–4.45 (m, 1H, CHI), 5.60 (d, J ¼ 8.0 Hz, 1H, CHO), 7.32–7.34 (m, 2H),
2
.39–7.41 (m, 3H). IR (KBr): 3036, 2950, 1723, 1205 cm . MS (EI, 30 eV):
1
7
m/z (%) 302 (6) [M ], 254 (17), 175 (100), 129 (30), 91 (95). Anal. Calcd. for
þ
C H IO : C 43.73 H 3.67, Found: C 43.47 H 3.56. Elemental analyses was
1
1
11
2
obtained with a mixture of two structural isomers 2a and 3a.
5
1
-(Iodo-p-tolyl-methyl)-dihydro-furan-2-one 2b. H NMR (300 MHz,
CDCl ): d ¼ 2.11–2.18 (m, 1H), 2.33 (s, 3H, CH ), 2.52–2.63 (m, 3H), 4.84–
3
3
4
7
.91 (m, 1H, CHO), 5.12 (d, J ¼ 8.0 Hz, 1H, CHI), 7.12 (d, J ¼ 8.0 Hz, 2H),
2
1
.31 (d, J ¼ 8.0 Hz, 2H). IR (KBr): 3050, 2989, 1759, 1185, 822 cm . MS
þ
(EI, 30 eV): m/z (%) 316 (2) [M ], 254 (38), 189 (98), 127 (20), 105 (100).
Anal. Calcd. for C H IO : C 45.59 H 4.14, Found: C 45.53 H 3.93.
1
2
13
2
Elemental analyses was obtained with a mixture of two structural isomers 2b
and 3b.
1
-Iodo-6-p-tolyl-tetrahydro-pyran-2-one 3b. H NMR (300 MHz,
5
CDCl ): d ¼ 2.35–2.50 (m, 2H), 2.39 (s, 3H, CH ), 2.67–2.77 (m, 1H),
3
3
2
.81–2.90 (m, 1H), 4.40–4.47 (m, 1H, CHI), 5.56 (d, J ¼ 8.0 Hz, 1H, CHO),
2
.23 (s, 4H). IR (KBr): 3031, 2951, 1727, 1201, 1016 cm . MS (EI, 30 eV):
1
7
m/z (%) 316 (2) [M ], 254 (39), 189 (100), 143 (34), 131 (38), 119 (53), 105
þ
(
75), 91 (18), 69 (35). Anal. Calcd. for C H IO : C 45.59 H 4.14, Found: C
12 13 2
45.53 H 3.93. Elemental analyses was obtained with a mixture of two
structural isomers 2b and 3b.
-(Iodo-o-tolyl-methyl)-dihydrofuran-2-one 2c. H NMR (300 MHz,
CDCl ): d ¼ 2.17–2.27 (m, 1H), 2.35 (s, 3H, CH ), 2.61–2.67 (m, 2H), 2.71–
1
5
3
3
2
.79 (m, 1H), 5.01–5.09 (m, 1H, CHO), 5.30 (d, J ¼ 7.5 Hz, 1H, CHI), 7.12
(
d, J ¼ 7.5 Hz, 1H), 7.15–7.24 (m, 2H), 7.51 (d, J ¼ 7.5 Hz, 1H). IR (KBr):
2
1
þ
3050, 2967, 1763, 1199 cm . MS (EI, 30 eV): m/z (%) 316 (5) [M ], 189
(70), 105 (100), 91 (18), 55 (30). Anal. Calcd. for C H IO : C 45.59 H 4.14,
12 13 2
Found: C 45.75 H 3.94. Elemental analyses was obtained with a mixture of
two structural isomers 2c and 3c.
5
1
-Iodo-6-o-tolyl-tetrahydro-pyran-2-one 3c. H NMR (300 MHz,
CDCl ): d ¼ 2.34–2.46 (m, 2H), 2.43 (s, 3H, CH ), 2.74–2.94 (m, 2H),
3
3
4
.43–4.50 (m, 1H, CHI), 5.81 (d, J ¼ 7.5 Hz, 1H, CHO), 7.20–7.29 (m, 4H).
2
1
IR (KBr): 3024, 2966, 1719, 1219 cm . MS (EI, 30 eV): m/z (%) 316 (4)

ORDER
REPRINTS
1
030
Wang et al.
þ
[M ], 254 (100), 189 (50), 127 (70), 105 (78), 55 (22). Anal. Calcd. for
C H IO : C 45.59 H 4.14, Found: C 45.75 H 3.94. Elemental analyses was
1
2
13
2
obtained with a mixture of two structural isomers 2c and 3c.
-Anthracen-9-yl-5-iodo-tetrahydro-pyran-2-one 3d.
1
6
H
NMR
(
(
300 MHz, CDCl ): d ¼ 2.86–3.09 (m, 4H), 5.33–5.39 (m, 1H, CHI), 7.04
3
d, J ¼ 10.5 Hz, 1H, CHO), 7.49 (dd, J ¼ 6.8 Hz, J ¼ 8.5 Hz, 2H), 7.57 (dd,
J ¼ 6.8 Hz, J ¼ 8.5 Hz, 2H), 8.08 (d, J ¼ 8.5 Hz, 2H), 8.30 (d, J ¼ 8.5 Hz,
2
1
H), 8.57 (s, 1H). IR (KBr): 3049, 2922, 1728, 1207, 1007, 729 cm . MS (EI,
2
7
þ
0 eV): m/z (%) 402 (2) [M ], 191 (100), 178 (32), 127 (38). Anal. Calcd. for
C H IO : C 56.74 H 3.76, Found: C 56.56 H 3.69.
1
9
15
2
1
-(p-Chloro-phenyl-iodo-methyl)-dihydrofuran-2-one 2e. H NMR
5
(
600 MHz, CDCl ): d ¼ 2.10–2.13 (m, 1H), 2.56–2.60 (m, 2H), 2.63–2.66
3
(
m, 1H), 4.87–4.91 (m, 1H, CHO), 5.05 (d, J ¼ 8.4 Hz, 1H, CHI), 7.30
(
d, J ¼ 8.4 Hz, 2H), 7.36 (d, J ¼ 8.4 Hz, 2H). IR (KBr): 3040, 2982, 1766,
2
1
þ
1
494, 1191, 833 cm . MS (EI, 30 eV): m/z (%) 337 (2) [M ], 254 (26), 211
(
30), 209 (100), 127 (56), 125 (70), 55 (32). Anal. Calcd. for C H ClIO : C
11 10 2
39.26 H 2.99 Cl 10.66, Found: C 39.68 H 2.82 Cl 11.32. Elemental analyses
was obtained with a mixture of two structural isomers 2e and 3e.
1
-(P-Chloro-phenyl)-5-iodo-tetrahydro-pyran-2-one 3e. H NMR
6
(
300 MHz, CDCl ): d ¼ 2.46–2.56 (m, 2H, CH ), 2.73–2.84 (m, 2H, CH ),
3
2
2
4
.30–4.38 (m, 1H, CHI), 5.50 (d, J ¼ 8.4 Hz, 1H, CHO), 7.31 (d, J ¼ 8.4 Hz,
2
1
2
H), 7.40 (d, J ¼ 8.4 Hz, 2H). IR (KBr): 3063, 2983, 1731, 1201, 1011 cm
.
þ
þ
MS (EI, 30 eV): m/z (%) 339 (8) [M þ 2], 337 (23) [M ], 211 (15), 209 (70),
1
63 (30), 69 (100), 55 (42). Anal. Calcd. for C H ClIO : C 39.26 H 2.99 Cl
11 10 2
10.66, Found: C 39.68 H 2.82 Cl 11.32. Elemental analyses was obtained with
a mixture of two structural isomers 2e and 3e.
1
-(1-Iodo-butyl)-dihydro-furan-2-one 2g. H NMR (300 MHz, CDCl ):
5
3
d ¼ 0.96 (t, J ¼ 7.4 Hz, 3H, CH ), 1.36–1.48 (m, 1H), 1.50–1.86 (m, 3H),
3
1
.95–2.10 (m, 1H), 2.48-2.64 (m, 3H), 4.10–4.16 (m, 1H, CHO), 4.34–4.41
2
m, 1H, CHI). IR (KBr): 2959, 1775, 1457, 1166, 1016 cm . MS (EI, 70 eV):
1
(
m/z (%) 268 (5) (M ), 141 (89), 85 (100). Anal. Calcd. for C H IO : C 35.84
H 4.89, Found: C 36.24 H 4.98.
þ
8
13
2
ACKNOWLEDGMENTS
We thank Prof. Meng Xian Ding and Prof. Qun Liu (Northeast Normal
University, China) and Dr. Peng Zhou (Kionix, Inc., USA) for their discussion
and advice.

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Reagent-Controlled Asymmetric Iodolactonization
REFERENCES
1031
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(
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Received in Japan July 7, 2003

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