A method for the synthesis of 3a-aryl-substituted cyclopenta[1,2-b]furan derivatives

Article abstract of DOI:10.1055/s-2005-922758

An alternative method for the synthesis of cyclopenta[1,2-b]furan (CPF) derivatives, which show promise as chiral resolving agents, was developed. Various CPF derivatives, aryl-substituted at the 3a-position, can be synthesized via Suzuki-Miyaura coupling reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-922758

LETTER
3103
A Method for the Synthesis of 3a-Aryl-Substituted Cyclopenta[1,2-b]furan
Derivatives
S
H
ynthesis of 3a-A
r
i
yl-Sub
s
C
y
a
clopenta[1
o
,2-
b
]furanDerivati
Nv es emoto,* Xian Peng, Weihui Zhong, Jun Xie, Tomoyuki Kawamura, Masaru Nishida
Division of Pharmaceutical Chemistry, Institute of Health Biosciences, Graduate School of the University of Tokushima, 1-78 Sho-machi,
Tokushima 770-8505, Japan
Fax +81(88)6337284; E-mail: nem@ph.tokushima-u.ac.jp
Received 22 August 2005
detected for the synthetic intermediates 6–10
Abstract: An alternative method for the synthesis of cyclo-
4
(
Scheme 2). It is reasonable to assume, therefore, this
penta[1,2-b]furan (CPF) derivatives, which show promise as chiral
resolving agents, was developed. Various CPF derivatives, aryl-
substituted at the 3a-position, can be synthesized via Suzuki–
Miyaura coupling reaction.
stereospecific controlled cis-fused relative stereochemis-
try strongly depends upon cyclopenta[1,2-b]furan (CPF)
framework, rather than the nature of the 3a-side chain.
Accordingly, CPF derivatives with different side chains
can serve as efficient and perhaps unique chiral resolving
agents.
Key words: cyclopenta[1,2-b]furan, chiral resolution, divergent
synthesis, secondary alcohols, acetals
OMe
OMe
OMe
Optically pure secondary alcohols are important compo-
nents in the production of pharmaceuticals, perfumes, dis-
plays of electronics, and synthetic intermediates. We
O
O
O
1
have described the preparation of a diastereomeric mix-
ture of the cis-fused acetals 2 and 3 produced from a dl-2-
alkanol and 3a-benzhydryl-2,3,4,5,3a-pentahydrocyclo-
penta[1,2-b]furan (1, CPF-Bzh) in the presence of a cata-
CHO
6
7
8
OMe
OMe
2
lytic amount of an acid (Scheme 1). The facile separation
O
O
Li/NH
3
of 2 and 3 by silica gel column chromatography demon-
strated that 1 can act as an efficient chiral resolving agent3
for 2-alkanols. Such stereospecific control of the acetal
1
Ph
O
Ph
Ph
OH
4
carbon affords an easy and practical separation process.
9
10
H3C
CnH2n+1
CnH2n+1
H3C
O
CnH2n+1
Scheme 2 Previously reported synthetic route of 1.
H3C
O
O
6
O
O
Several problems are associated with the previous syn-
thetic route for 1. First, the transformation from 6 to 1 re-
quires numerous steps. Secondary, the allyl group of 6,
which was introduced for the convenience of palladium-
2
5
OH
cis-
junctured
3
4
5
1
2
3
catalyzed reaction from 12 to 13, limits the introduction
of various side chains in place of allyl group (Scheme 3).
H3C
O
CnH2n+1
H3C
O
CnH2n+1
O
O
Herein, we report an alternative method for the divergent
synthesis of CPF derivatives (Scheme 4). Nucleophilic
addition of 4-bromophenyllithium to cyclopentanone at
trans-
junctured
–
78 °C for 4 hours, followed by dehydration of the result-
ing tertiary alcohol with p-toluenesulfonic acid gave 14 in
7% yield. Treatment of 14 with hydrogen peroxide and
7
4
5
formic acid in well-stirred benzene–water at 35 °C for 4
hours gave 15 in 45% yield. The conditions for these two
Scheme 1 Previously reported reaction of 1 with 2-alkanols.
reactions were based on the reported procedures for 2-
5
To the best of our knowledge, the formation of trans- phenylcyclopenta-1-one. Attempts to alkylate the enolate
fused diastereomers 4 and 5 has yet to be observed. Not from 15 included the use of lithium-, sodium-, potassium
hexamethyl disilazide, lithium diisopropylamide, and
sodium hydride as the base. These reactions, however,
resulted in the formation of unidentified products; more-
over, compound 15 was not quantitatively recovered.
Subsequently, the successful alkylation of 15 involved the
even trace amounts of trans-fused diastereomer have been
SYNLETT 2005, No. 20, pp 3103–3106
1
9
.1
2
.2
0
0
5
Advanced online publication: 28.11.2005
DOI: 10.1055/s-2005-922758; Art ID: U26405ST
©
Georg Thieme Verlag Stuttgart · New York

3
104
H. Nemoto et al.
LETTER
O
O
O
I
AcO
Pd cat.
AcO
AcO
6
O
O
O
O
12
13
11
Scheme 3 Previously reported preparation of 6 having CPF framework.
use of 2-bromoethyl acetate with sodium hydroxide and by column chromatography on silica gel (hexane–
tetrabutylammonium iodide in refluxing and vigorously EtOAc = 9:1) to give 18b as a colorless solid (2.00 g, 4.96
stirred biphasic benzene–water solution. Formation of a mmol, 76% yield).
carbon–carbon bond occurred only at the benzylic posi-
7
To assess its ability as a chiral resolving agent, 18 was
tion probably because the pK value of 15 at the benzylic
a
converted into a mixture of two diastereomers of acetal
9 using 2-octanol. The reaction was carried out in
toluene at reflux in the presence of a catalytic amount of
methyne is expected to be lower than at the opposite side
of methylene. Finally, the crude mixture was treated with
p-toluenesulfonic acid in methanol to give a desired CPF
derivative 16 (55% overall yield from 15).
8
1
pyridinium p-toluene sulfonate.
The chemical yields form 17 to 18, 18 to 19, and DRf
values of 19a–d by silica gel thin layer chromatography9
OMe
O
O
b
c
are listed in Table 1. For comparison, the DR value of a
f
a
mixture of diastereomers, 1a-(2-octyloxyl)-substituted
acetals, which were prepared from 1, 6, 7 and 16, are also
included. Among the derivatives, three show improved
efficiencies as chiral resolving agents in comparison to 1
O
Br
Br
14
15
16
Br
(
entries 2–4).
a: Ar =
b: Ar =
Ar B(OH)2
d
17
Table 1 The DR Value of 19 Eluted with Hexane–Toluene (1:1),
f
H3C
O
C6H13
Chemical Yields from 17 to 18, and from 18 to 19
O
OMe
O
Entry
Acetal
Yield from 17 Yield from 18 DR of two
f
e
c: Ar =
d: Ar =
to 18 (%)
to 19 (%)
diastereomeric
acetals 19
1
2
3
4
5
6
7
8
18a
18b
18c
18d
1
74
76
37
65
–
68
67
76
72
–
0.083
0.121
0.110
0.113
0.099
0.100
0.100
0.000
1
9
18
Ar
Ar
Scheme 4 An alternative method for the synthesis of CPF deriva-
tives 18. Reagents and conditions: a) 4-BrC H Li in THF, –78 °C to
r.t., 4 h; p-TsOH in benzene, reflux, 3.5 h; b) H O –HCO H, 35 °C, 4
6
4
2
2
2
h; c) BrCH CH OAc/Bu NI/NaOH, in benzene–H O, reflux, 6 h; p-
2
2
4
2
TsOH in MeOH, reflux, 5 h; d) Pd(OAc) /Na CO /PPh in PrOH–
2
2
3
3
H O, reflux, 5 h; e) 2-octanol (2 equiv) in toluene at reflux, PPTS, 3 h.
2
6
–
–
In our synthetic scheme, bromide 16 serves as the diverg-
ing intermediate for the synthesis of 18 with various aryl
groups. Accordingly, the synthesis of compounds 18a–d
7
–
–
16
–
–
were carried out using the corresponding arylboronic ac-
6
ids 17a–d via Suzuki–Miyaura coupling reaction. Details In conclusion, an alternative route for the synthesis of
10
of a typical experimental procedure are as follows: a mix- CPF derivatives bearing 3a-aryl substituent was devel-
ture of 16 (2.00 g, 6.53 mmol), 17b (1.90 g, 8.49 mmol), oped. Consequently, several new CPF derivatives, which
palladium acetate (15 mg, 0.065 mmol), triphenylphos- show promise as chiral resolving agents, were synthe-
phine (52 mg, 0.198 mmol), and sodium carbonate (8 mL sized. Additional divergent syntheses of various CPF de-
of a 2 M solution in H O, 9.43 mmol) in propanol (25 mL) rivatives and their evaluation are currently underway.
2
was refluxed with stirring for 5 hours. The resulting mix-
ture was poured into water (50 mL), then extracted with
diethyl ether (3 × 15 mL). The combined organic layers
Acknowledgment
were washed with water, brine, dried over magnesium sul- We thank Nihon Zeon Co Ltd. and NEDO (New Energy and Indus-
fate, and concentrated in vacuo. The residue was purified trial Technology Development Organization) for their financial
support.
Synlett 2005, No. 20, 3103–3106 © Thieme Stuttgart · New York

LETTER
Synthesis of 3a-Aryl-Substituted Cyclopenta[1,2-b]furan Derivatives
3105
References
(9) TLC used in all the experimental was obtained from Merck
1.05715.0009, silica gel 60F254).
10) Data of four CPF derivatives synthesized by Suzuki–
Miyaura coupling reaction and their synthetic intermediates
are as following.
(
(
1) (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
Compound 14: colorless crystals; mp 94–95 °C (hexane).
FT-IR (KBr): 3053, 2953, 2843, 1902, 1619, 1585, 1486
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.
–1
1
cm . H NMR (400 MHz, CDCl ): d = 7.41 (d, J = 8.4 Hz,
3
2
2
H), 7.27 (d, J = 8.4 Hz, 2 H), 6.17 (s, 1 H), 2.68–2.63 (m,
H), 2.53–2.48 (m, 2 H), 2.01 (td, J = 14.8, 7.6 Hz, 2 H). C
13
NMR (100 MHz, CDCl ): d = 141.3 (C), 135.7 (C), 131.2
3
(
2) Previously reported acetal-type chiral reagents and the
related one. See: (a) Wuts, P. G. M.; Bigelow, S. S. J. Chem.
Soc., Chem. Commun. 1984, 736. (b) Noe, C. R.;
(
2 × CH), 127.1 (2 × CH), 127.0 (CH), 120.5 (C), 33.5
(CH ), 33.2 (CH ), 23.4 (CH ). HRMS (EI): m/z calcd for
2
2
2
+
C H Br [M ]: 222.0044; found: 222.0060. Anal. Calcd for
1
1
11
Knollmüller, M.; Steinbauer, G.; Jangg, E.; Völlenkle, H.
Chem. Ber. 1988, 121, 1231. (c) Linderman, R. J.; Cusack,
K. P.; Jaber, M. R. Tetrahedron Lett. 1996, 37, 6649.
C H Br: C, 59.22; H, 4.97. Found: C, 58.91; H, 4.94.
1
1
11
Compound 15: colorless oil. FT-IR (KBr): 3029, 2966,
–1
1
2
876, 1899, 1741, 1589, 1488, 1402 cm . H NMR (400
(
d) Lainé, D.; Fujita, M.; Lay, S. V. J. Chem. Soc., Perkin
MHz, CDCl ): d = 7.44 (d, J = 8.4 Hz, 2 H), 7.06 (d, J = 8.4
3
Trans. 1 1999, 1639. (e) Mori, K.; Uematsu, T.; Minobe,
M.; Yanagi, K. Tetrahedron Lett. 1982, 23, 1921.
Hz, 2 H), 3.26 (dd, J = 11.4, 8.0 Hz, 1 H), 2.51–2.42 (m, 2
H), 2.31–2.21 (m, 1 H), 2.18–2.10 (m, 1 H), 2.08–2.00 (m, 1
(f) Buchanan, D. J.; Dixon, D. J.; Hernandez-Juan, F. A.
13
H), 1.95–1.85 (m, 1 H). C NMR (100 MHz, CDCl ): d =
3
Org. Lett. 2004, 6, 1357.
2
17.0 (C), 137.1 (C), 131.5 (2 × CH), 129.7 (2 × CH), 120.7
(
3) Nemoto, H.; Tsutsumi, H.; Yuzawa, S.; Peng, X.; Zhong,
W.; Xie, J.; Miyoshi, N.; Suzuki, I.; Shibuya, M.
Tetrahedron Lett. 2004, 45, 1667.
(
C), 54.6 (CH), 38.2 (CH ), 31.4 (CH ), 20.8 (CH ). HRMS
2 2 2
+
(
EI): m/z calcd for C H BrO [M ]: 237.9993; found:
11 11
237.9996.
(
(
4) Nemoto, H. Tetrahedron Lett. 1994, 35, 7855.
5) Mazzocchiu, P. H.; Kim, C. H. J. Med. Chem. 1982, 25,
Compound 16: colorless crystals; mp 48–49 °C (hexane).
–1
1
FTIR (KBr, CHCl ): 2955, 2829, 1489, 1316 cm . H NMR
3
1473.
(
400 MHz, CDCl ): d = 7.41 (d, J = 8.8 Hz, 2 H), 7.25 (d,
3
(
(
6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
7) We did not carry out the transformation reaction from 18 to
the corresponding alkenyl ethers for the following reasons.
J = 8.8 Hz, 2 H), 4.05 (t, J = 7.2 Hz, 2 H), 3.20 (s, 3 H),
2
.49–2.42 (m, 1 H), 2.29–2.22 (m, 2 H), 1.98–1.89 (m, 3 H),
13
1
.83–1.76 (m, 2 H). C NMR (100 MHz, CDCl ): d = 143.4
3
1) In a cooperative work with Zeon Corporation, exhaustive
(
C), 130.8 (2 × CH), 129.1 (2 × CH), 119.8 (C), 118.1 (C),
optimizations in industrial-scale were carried out for alcohol
exchange reaction of acetal 6 and various dl-secondary
alcohols. As a result, several dl-alcohols were converted to
the corresponding diastereomers in excellent yields with
high cost performance. Thus, priority of the optimization of
acetal exchange reaction in laboratory scale is low. 2) We
attempted the transformation reaction from 20 or 21 to the
corresponding alkenyl ethers, and the carbon–carbon bond
cleavage reactions were observed as shown in the following
scheme. Conversely, we consider that possibility of such
cleavage reactions for 18a–d is very low (Scheme 5).
66.2 (CH ), 58.6 (C), 50.9 (CH ), 40.3 (CH ), 38.1 (CH ),
2 3 2 2
3
4.3 (CH ), 21.4 (CH ). HRMS (EI): m/z calcd for
2
2
+
C H BrO [M ]: 296.0412; found: 296.0402. Anal. Calcd
1
4
17
2
for C H BrO : C, 56.58; H, 5.77. Found: C, 56.43; H, 5.67.
1
4
17
2
Compound 18a: colorless solid; mp 155–156 °C (EtOAc–
hexane). FT-IR (KBr): 3027, 2948, 2880, 2829, 1605, 1515,
–1
1
1
495, 1447, 1426, 1366 cm . H NMR (400 MHz, CDCl ):
3
d = 7.76 (d, J = 8.0 Hz, 1 H), 7.52–7.47 (m, 4 H), 7.41 (d,
J = 7.2 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 2 H), 7.31 (d, J = 12.4
Hz, 1 H), 7.29 (d, J = 12.4 Hz, 1 H), 4.15–4.06 (m, 2 H), 3.41
(
s, 4 H), 3.27 (s, 3 H), 2.62–2.55 (m, 1 H), 2.37–2.27 (m, 2
1
3
H), 2.13–1.98 (m, 3 H), 1.94–1.80 (m, 2 H). C NMR (100
OMe
OMe
OMe
MHz, CDCl ): d = 146.0 (C), 145.3 (C), 143.1 (C), 139.5
3
O
O
OH
(
C), 137.4 (C), 135.4 (C), 129.7 (C), 129.1 (2 × CH), 128.5
O
(CH), 127.8 (CH), 127.2 (2 × CH), 121.0 (C), 119.1 (CH),
1
18.4 (CH), 66.2 (CH ), 58.8 (C), 50.9 (CH ), 40.7 (CH ),
2
3
2
H+
O
Ph
38.1 (CH ), 34.4 (CH ), 30.6 (CH ), 30.1 (CH ), 21.5 (CH ).
HO
Ph
2 2 2 2 2
O
Ph
20
+
HRMS (EI): m/z calcd for C H O [M ]: 370.1933; found:
2
6
26
2
3
70.1953. Anal. Calcd for C H O : C, 84.29; H, 7.07.
H+
26 26 2
H
Found: C, 84.56; H, 7.21.
OMe
OMe
O
Compound 18b: colorless solid; mp 144–145 °C (EtOAc–
O
O
HO
hexane). FT-IR (KBr): 2950, 2881, 2828, 2244, 1610, 1510,
–
1 1
1
8
492, 1450, 1317 cm . H NMR (400 MHz, CDCl ): d =
3
.76 (d, J = 8.0 Hz, 1 H), 8.70 (d, J = 8.0 Hz, 1 H), 8.00 (d,
Ph
Ph
O
H
Ph
Ph
J = 8.0 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.68–7.57 (m, 4
H), 7.54–7.47 (m, 5 H), 4.16–4.07 (m, 2 H), 3.29 (s, 3 H),
O
21
2
.64–2.57 (m, 1 H), 2.39–2.28 (m, 2 H), 2.15–2.00 (m, 3 H),
Scheme 5
13
1
.92–1.82 (m, 2 H). C NMR (100 MHz, CDCl ): d = 143.5
3
(
C), 138.6 (C), 138.1 (C), 131.6 (C), 131.1 (C), 130.6 (C),
(
8) In the case of 2 and 3 (CPF-Bzh derivatives of 2-alkanols),
the absolute configuration of the 2-alkoxy position can be
empirically determined by the chemical shift of benzylic
position, which appears around at d = 4.5–4.6 ppm as a clear
1
×
29.8 (C), 129.5 (2 × CH), 128.6 (CH), 127.5 (CH), 127.2 (2
CH), 127.0 (CH), 126.7 (CH), 126.43 (CH), 126.36 (2 ×
CH), 122.8 (CH), 122.5 (CH), 118.4 (C), 66.3 (CH ), 58.9
2
(
(
C), 51.0 (CH ), 40.7 (CH ), 38.2 (CH ), 34.4 (CH ), 21.5
CH ). HRMS (EI): m/z calcd for C H O [M ]: 394.1933;
3 2 2 2
1
13
singlet in H NMR and around at d = 60–71 ppm in
C
+
2
28 26
2
1
NMR. In contrast, no such peak was observed in H NMR
found: 394.1954. Anal. Calcd for C H O : C, 85.25; H,
2
8
26
2
and 13C NMR of 19.
6.64. Found: C, 85.60; H, 6.85.
Synlett 2005, No. 20, 3103–3106 © Thieme Stuttgart · New York

3
106
H. Nemoto et al.
LETTER
Compound 18c: colorless solid; mp 225–226 °C (EtOAc–
Compound 18d: light yellow crystals; mp 196–197 °C
(EtOAc–hexane). FT-IR (KBr): 2955, 2828, 1917, 1796,
1601, 1584, 1520, 1499, 1402 cm . H NMR (400 MHz,
hexane). FT-IR (KBr): 3048, 2971, 2886, 2830, 1815, 1621,
–
1
1
–1 1
1
514, 1441, 1412, 1362, 1319 cm . H NMR (400 MHz,
CDCl ): d = 8.48 (s, 1 H), 8.03 (d, J = 8.4 Hz, 2 H), 7.73 (d,
CDCl ): d = 8.24 (d, J = 9.2 Hz, 1 H), 8.18 (d, J = 8.0 Hz, 1
3
3
J = 8.4 Hz, 2 H), 7.58 (d, J = 8.0 Hz, 2 H), 7.45 (t, J = 7.6
Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.34 (t, J = 7.6 Hz, 2 H),
H), 8.14 (t, J = 8.0 Hz, 2 H), 8.05 (s, 2 H), 8.00–7.95 (m, 3
H), 7.57–7.52 (m, 4 H), 4.16–4.06 (m, 2 H), 3.30 (s, 3 H),
2.64–2.57 (m, 1 H), 2.38–2.28 (m, 2 H), 2.15–2.00 (m, 3 H),
4
2
1
1
.21–4.11 (m, 2 H), 3.32 (s, 3 H), 2.71–2.63 (m, 1 H), 2.46–
1
3
.40 (m, 1 H), 2.38–2.31 (m, 1 H), 2.22–2.04 (m, 3 H), 2.00–
1.93–1.81 (m, 2 H). C NMR (100 MHz, CDCl ): d = 143.4
3
.85 (m, 2 H). 1 C NMR (100 MHz, CDCl ): d = 143.7 (C),
3
(C), 138.5 (C), 137.8 (C), 131.4 (C), 131.0 (C), 130.4 (C),
130.0 (2 × CH), 128.4 (C), 127.6 (CH), 127.4 (CH), 127.28
(3 × CH), 127.26 (CH), 127.24 (C), 125.9 (CH), 125.5 (CH),
124.95 (CH), 124.9 (C), 124.7 (CH), 124.6 (CH), 118.4 (C),
66.3 (CH ), 58.9 (C), 51.0 (CH ), 40.7 (CH ), 38.2 (CH ),
3
37.0 (C), 135.9 (C), 131.4 (2 × C), 130.7 (2 × CH), 130.3
(
1
2 × C), 128.2 (2 × CH), 127.2 (2 × CH), 127.0 (2 × CH),
26.4 (CH), 125.1 (2 × CH), 125.0 (2 × CH), 118.5 (C), 66.4
(CH ), 59.0 (C), 51.0 (CH ), 41.1 (CH ), 38.2 (CH ), 34.7
2
3
2
2
2
3
2
2
(
[
CH ), 21.6 (CH ). HRMS (EI): m/z calcd for C H O
34.4 (CH ), 21.5 (CH ). HRMS (EI): m/z calcd for C H O
[M ]: 418.1933; found: 418.1941. Anal. Calcd for C H O :
30 26 2
2
2
28 26
2
2 2 30 26 2
+
+
M ]: 394.1933; found: 394.1954. Anal. Calcd for C H O :
2
8
26
2
C, 85.25; H, 6.64. Found: C, 85.20; H, 6.77.
C, 86.09; H, 6.26. Found: C, 85.93; H, 6.37.
Synlett 2005, No. 20, 3103–3106 © Thieme Stuttgart · New York