An efficient method for the synthesis of hydrocyclopenta[1,2-b]furan with various side chains at 3a-position

Article abstract of DOI:10.1016/j.tetlet.2005.07.164

(3aS*,1aR*)-1a-Methoxy-3a-methoxycarbonyl-2,3,4,5,6, 3a-hexahydrocyclopenta[1,2-b]furan was prepared in 96% overall yield from 2-methoxycarbonylated cyclopenta-1-one in two steps. This furan derivative is used as a divergent intermediate in the synthesis of our originally designed chiral resolving agents having various substitutions. During the preliminary evaluation of divergent synthetic products, it was discovered that 3a-(fluoren-9-ylidenemethyl)-2,3,4,5,3a-pentahydrocyclopenta[1,2-b]furan, was a remarkably improved chiral resolving agent for secondary alcohols.

Full text of DOI:10.1016/j.tetlet.2005.07.164

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7451–7454
An efficient method for the synthesis of
hydrocyclopenta[1,2-b]furan with various side chains at 3a-position
Weihui Zhong, Jun Xie, Xian Peng, Tomoyuki Kawamura and Hisao Nemoto*
Division of Pharmaceutical Chemistry, Institution of Health Biosciences, Graduate School of The University of Tokushima, 1-78,
Sho-machi, Tokushima 770-8505, Japan
Received 17 June 2005; revised 19 July 2005; accepted 29 July 2005
Available online 9 September 2005
Abstract—(3aS ,1aR )-1a-Methoxy-3a-methoxycarbonyl-2,3,4,5,6,3a-hexahydrocyclopenta[1,2-b]furan was prepared in 96% over-
*
*
all yield from 2-methoxycarbonylated cyclopenta-1-one in two steps. This furan derivative is used as a divergent intermediate in the
synthesis of our originally designed chiral resolving agents having various substitutions. During the preliminary evaluation of diver-
gent synthetic products, it was discovered that 3a-(fluoren-9-ylidenemethyl)-2,3,4,5,3a-pentahydrocyclopenta[1,2-b]furan, was a
remarkably improved chiral resolving agent for secondary alcohols.
Ó 2005 Published by Elsevier Ltd.
Chiral resolution is one of the major methods1–4 used to
obtain optically active secondary alcohols. The avail-
ability of these compounds is important in the produc-
tion of pharmaceutical products, perfumes, displays of
electronics, and various synthetic intermediates.5 We
have reported chiral resolution of dl-2-alkanols by using
3a-benzhydryl-2,3,4,5,3a-pentahydrocyclopenta[1,2-b]-
furan 1 (CPF-Bzh)6 via a mixture of two (not four)
cis-fused diastereomeric acetals7 2, which were easily
separated by the usual method of silica gel chromato-
graphy (Scheme 1).8 However, many steps were required
for the synthesis of 1,8 and three intricate reactions9
(two of palladium-catalyzed reactions and an ozonoly-
sis) were involved. Furthermore, for the sake of high
performance of chiral resolution, there are no grounds
for choice of Bzh group. Thus, a novel, more efficient
synthetic route should be developed to produce CPF
derivatives having various side chains, in order to
achieve a highly efficient chiral resolution.
We report here, the syntheses of new derivatives 7–9 in
short steps, and their performance with respect to chiral
resolution (Scheme 2). The intermediate 6, which occurs
at the diverging point for the synthesis of various CPF
derivatives, was obtained from commercially available
material 3 in two steps, so that this synthesis could be
easily carried out on a large scale. Alkylation of 4 to 3
with suspended potassium carbonate gave 5 in 98%
yield. Treatment of 5 with a catalytic amount of p-tolu-
ene sulfonic acid (p-TsOH) in methanol gave 6 in 98%
yield.
Next, we examined transformation reactions in which
various substitutions were made at the methoxycarbonyl
group of 6. To simplify the design of compounds that
would influence the chiral resolving property through
the side chains, we synthesized preliminary compounds
H C
3
C H
n 2n+1
H C
3
C H
n 2n+1
H C
3
C H
n 2n+1
6
O
O
O
3
OH
O
O
2
5
4
1
K CO
2
3
in acetone
rt, 3 h
p-TsOH
in methanol
OMe
2
O
O
O
Scheme 1.
rt, 12 h
98%
I
MeO C
2
AcO
AcO
CO Me
2
4
CO Me
2
( )-5
( )-3
98%
( )-6
*
Corresponding author. Tel./fax: +81 88 633 7284; e-mail: nem@ph.
tokushima-u.ac.jp
Scheme 2. Rt = room temperature.
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.07.164

7452
W. Zhong et al. / Tetrahedron Letters 46 (2005) 7451–7454
C6H13
O
OMe
O
O
85%
a
63%
d
∆Rf = 0.113
10
( )-7
C6H13
O
OMe
O
O
∆Rf = 0.138
56%
b
76%
d
( )-6
11
( )-8
C6H13
O
OMe
O
O
26%
d
95%
c
∆Rf = 0.106
12
( )-9
O
C6H13
HO
O
O
∆Rf = 0.099
13
14
Scheme 3. Reagents and conditions: (a) MeLi in THF, 0 °C, 1 h, methanesulfonyl chloride in pyridine, 0 °C, 1 h; (b) diisobutylaluminium hydride in
THF, 2 h, 0 °C, 9-lithiofluorene in THF, 60 °C, 6 h; (c) 6C6H5C6H5Li in THF, 2 h, 0 °C, Li/NH3, 1 h, Pd/C, H2 in AcOEt, 1 h; (d) 2-octanol
(1.1 equiv), pyridinium p-toluenesulfonate in toluene, reflux, 3 h.
having various side chains without an asymmetric center
or a geometrical isomer at the double bond (Scheme 3).
compounds 10, 11, and 12 (0.113, 0.138, and 0.106,
respectively) were larger than the previously reported
DRf value of 13 (0.099).8 This indicates a possibility that
additional improved chiral resolving agents11 may be
discovered via the divergent intermediate 6.
Double alkylations of 6 with methyllithium followed by
elimination of the resulting hydroxyl group via mesylate
gave 7 in 85% yield. Reduction of 6 with DIBAL-H in
THF at ꢀ78 °C followed by addition of 9-lithiofluorene
to the resulting aldehyde gave 8 in 95% yield. Addition
of two 4-phenylphenyllithium to the ester 6 followed
by the treatment with Li/NH3 gave 9 in 56% overall
yield from 6.
Since the largest DRf value among all the compounds
examined was recorded by using 8, optically active 15
was prepared to examine the DRf value of a diastereo-
meric acetal with various secondary alcohols (Scheme
4). The diastereomeric mixture of acetal 11 prepared
from (ꢀ)-2R-octanol and ( )-8, was separated by sil-
Acid-catalyzed alcohol-exchange reactions were exam-
ined for their ability to substitute the methoxy group
for the 2-octyloxy group of 7–9, and evaluate the prop-
erties of the resulting molecules. The corresponding dia-
stereomeric acetals 10 and 11 were obtained from 7 and
8 in toluene in the presence of a catalytic amount of
pyridinium 4-toluenesulfonate (PPTS) after reflux for
3 h, giving yields of 63% and 76% yield, respectively
(Scheme 3). However, the alcohol exchange reaction
gave 12 from 9 in low yield along with several unidenti-
fied byproducts including probably keto alcohol 14. This
occurred even though many conditions were attempted
at varying temperatures, acid catalysts, solvents, and
so on, probably because of steric hindrance due to the
side chain. The DRf values of the obtained diastereomers
on silica gel thin-layer chromatography (TLC)10 are
appended in Scheme 3. Fortunately, in spite of the
preliminary survey, the DRf value of newly synthesized
ica gel column chromatography. The less polar com-
20
pound (ꢀ)-11a (½aꢁD ꢀ59.1,
c 1.50, CHCl3) was
20
transformed to (ꢀ)-8 (½aꢁD ꢀ42.1, c 0.247, CHCl3) with
methanol in the presence of a catalytic amount of PPTS.
The acetal (ꢀ)-8 was converted to the alkenyl ether (ꢀ)-
20
15 (½aꢁD ꢀ9.5, c 0.647, CHCl3) with acetyl chloride,
followed by treatment with triethylamine8 in 84% yield.
Transformation of the corresponding enantiomer from
20
20
(ꢀ)-11b (½aꢁD +0.8, c 1.44, CHCl3) to (+)-15 (½aꢁD +9.5,
c 0.962, CHCl3) was also carried out by the same
procedure.
A survey of the chiral resolving property of (ꢀ)-15 is
shown in Table 1 and compared with that of ordinary
alkenyl ether (ꢀ)-1.
All of the DRf values obtained from a mixture of two
diastereomers 17, which were derived from 15 and 2-alk-

W. Zhong et al. / Tetrahedron Letters 46 (2005) 7451–7454
7453
OMe
C H
6
13
O
O
O
O
a
b
95%
84%
(-)-8
(-)-15
(-)-11a
Column
separation
11
OMe
C H
6
13
O
O
O
O
a
b
95%
85%
(+)-15
(+)-8
(+)-11b
Scheme 4. Reagents and conditions: (a) p-TsOH in methanol, rt, 1 h; (b) AcCl in CHCl3, rt, 20 h, Et3N in CH2Cl2, reflux, 2 h.
Table 1. DRf values of two diastereomers on TLC8
Supplementary data
R1 R2
All the detailed descriptions of experimental procedures,
full characterization of compounds, and determination
of absolute configuration of (ꢀ)-15 and (+)-15. Supple-
mentary data associated with this article can be found,
in the online version at doi:10.1016/j.tetlet.2005.07.164.
R1 R2
OH
O
R
O
O
R
PPTS, CH2Cl2
(-)-1: R = benzhydryl
(-)-15: R = fluoren-9-ylidenemethyl
16: R = benzhydryl
17: R = fluoren-9-ylidenemethyl
References and notes
Entry
Secondary alcohol
(R1CH(OH)R2)
DRf of 16 DRf of 17
1. Metal-catalyzed oxidative kinetic resolution. Nishiba-
yashi, Y.; Yamauchi, A.; Onodera, G.; Uemura, S. J.
Org. Chem. 2003, 68, 5875–5880.
2. Biocatalyzed oxidative kinetic resolution. Stampfer, W.;
Kosjek, B.; Faber, K.; Kroutil, W. Tetrahedron: Asym-
metry 2003, 14, 275–280.
R1
R2
1
2
3
4
5
6
7
CH3
CH3
CH3
CH3
CH3
C3H7
C4H9
C5H11
C9H19
C13H27
0.045
0.082
0.091
0.147
0.153
0.000
0.053
0.090
0.111
0.156
0.168
0.050
0.050
3. Enzyme-catalyzed selective esterification of alcohols. (a)
Oshitari, T.; Mandai, T. Synlett 2003, 2374–2376; (b)
b-Naphthyl C3H7
C6H5
`
Pamies, O.; Ba¨ckvall, J. Adv. Synth. Catal. 2002, 344, 947–
952; (c) Pamiers, O.; Ba¨ckvall, J. J. Org. Chem. 2001, 66,
(CH2)3CO2Me 0.000
`
Eluent: hexane–toluene = 1:1 (entries 1–6).
Eluent: hexane–ethyl acetate = 5:1 (entry 7).
4022–4025.
4. Chiral-polymer-supported scavenging of sec-alcohols.
´
Cordova, A.; Tremblay, M. R.; Clapham, B.; Janda, K.
D. J. Org. Chem. 2001, 66, 5645–5648.
anols (entries 1–5 and appended value in Scheme 3 for 2-
octanol) were larger than the corresponding 16 obtained
from 1. We next have examined certain secondary alco-
hols bearing an aromatic ring. By using 1, only one spot
was observed on TLC (entries 6 and 7). In contrast, by
using 15, two distinct spots corresponding to the diaste-
reomers were clearly observed on TLC.
5. (a) Chirality in Industry: The Commercial Manufacture and
Applications of Optically Active Compounds; Collins, A.
D., Sheldrake, G. N., Crosby, J., Eds.; Wiley: Chichester,
1992; (b) Chirality in Industry II: Developments in the
Commercial Manufacture and Applications of Optically
Active Compounds; Collins, A. D., Sheldrake, G. N.,
Crosby, J., Eds.; Wiley: Chichester, 1997; (c) Sheldon, R.
A. Chirotechnology: Industrial Synthesis of Optically
Active Compounds; Dekker: New York, 1993.
In conclusion, we have developed a more efficient route
for the synthesis of CPF derivatives via 6, and a promis-
ing new CPF derivative 15, and this method has a remark-
ably improved chiral resolving property.11 We are now in
a position to carry out further divergent syntheses of var-
ious CPF derivatives and evaluate their properties.
6. In this paper, ÔCPF derivativeÕ indicates both 3a-R-
2,3,4,5,3a-pentahydrocyclopenta[1,2-b]furan (alkenyl ether
form, CPF-R), and 3a-R-5a-OR0-perhydrocyclopenta[1,2-b]-
furan (acetal form, R0O-CPF-R).
OR'
O
O
R
R
Acknowledgments
CPF-R
R'O-CPF-R
We thank Zeon Corporation and NEDO (New Energy
and Industrial Technology Development Organization)
for their financial support.
7. Chiral resolution of dl-alcohol via diastereomeric esters
has been a major method. An example via esters: Kasai,
Y.; Naito, J.; Kuwahara, S.; Watanabe, M.; Ichikawa, A.;

7454
W. Zhong et al. / Tetrahedron Letters 46 (2005) 7451–7454
Harada, N. J. Synth. Org. Chem., Jpn. (Yuuki Gousei
the industrial scale. In the cases of palladium-catalyzed
reactions, recovery of expensive transition-metal is often
required for economical reason.
Kagaku Kyoukai-shi, Special Issue in Eng.) 2004, 62, 1114–
1127; A rare example via acetal: Mori, K.; Uematsu, T.;
Minobe, M.; Yanagi, K. Tetrahedron Lett. 1982, 23, 1921–
1924.
10. TLC used in all the experimental was obtained from
Merck (1.05715.0009, Silica gel 60F254).
8. Nemoto, H.; Tsutsumi, H.; Yuzawa, S.; Peng, X.; Zhong,
W.; Xie, J.; Miyoshi, N.; Suzuki, I.; Shibuya, M. Tetra-
hedron Lett. 2004, 45, 1667–1670.
9. The intermediate, ozonide, is an explosive chemical, and
has very low energical efficiency for the generation of
ozone gas. Therefore, ozonolysis is very unsuitable step for
11. Our chiral resolving method has been carried out in Zeon
Corporation and separation of several hundred kilograms
of diastereomers has been demonstrated even when non-
polar solvents were used. During the industrial scale work,
we observed that DRf value of TLC correlates closely with
practical separating efficiency.