Highly efficient chiral resolution and determination of absolute configuration of 2-alkanols by using a cyclopenta[b]furan derivative

Article abstract of DOI:10.1016/j.tetlet.2003.12.104

The reaction of 3a-benzhydryl-3,3a,4,5-tetrahydro-2H-cyclopenta[b]furan and various 2-alkanols in the presence of a catalytic amount of pyridinium 4-tolunesulfonate in dichloromethane gave 3a-benzhydryl-6a-(1-methyl-aloxy)- hexahydrocyclopenta[b]furan in

Full text of DOI:10.1016/j.tetlet.2003.12.104

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1667–1670
Highly efficient chiral resolution and determination of absolute
configuration of 2-alkanols by using a cyclopenta[b]furan
derivativeq
Hisao Nemoto,a,* Hiroe Tsutsumi,a Satomi Yuzawa,a Xian Peng,a Weihui Zhong,a
Jun Xie,a Norikazu Miyoshi,b Ichiro Suzukia and Masayuki Shibuyaa
aFaculty of Pharmaceutical Sciences, The University of Tokushima, 1-78, Sho-machi, Tokushima 770-8505, Japan
bDepartment of Chemistry, Faculty of Integrated Arts and Sciences, The University of Tokushima,
1-1, Minamijosanjima-cho, Tokushima 770-8502, Japan
Received 8 November 2003; revised 15 December 2003; accepted 18 December 2003
Abstract—The reaction of 3a-benzhydryl-3,3a,4,5-tetrahydro-2H-cyclopenta[b]furan and various 2-alkanols in the presence of a
catalytic amount of pyridinium 4-tolunesulfonate in dichloromethane gave 3a-benzhydryl-6a-(1-methyl-aloxy)-hexahydrocyclo-
penta[b]furan in more than 90% chemical yields. The resulting diastereomeric mixture is easily separable on silica gel chromato-
graphy because of the large DRf value (briefly 0.1). Absolute configuration of the 2-alkanols can be easily estimated by the chemical
1
shifts of H and 13C NMR of methyne group of the benzhydryl moiety.
Ó 2003 Elsevier Ltd. All rights reserved.
One of the most efficient methods of resolving an
enantiomeric mixture of amines or acids is by recrys-
tallization as their diastereomeric salts using an optically
pure counterpart.1
which is then resolved by recrystallization or chroma-
tography (Scheme 1).1;2 An alternate approach to
resolve chiral alcohols is by the formation of acetals
(e.g., 5) with chiral alkenyl ethers (e.g., 4); however, this
method has not been widely reported.3 One of the seri-
ous problems of this method is the lack of control of the
stereochemistry of the newly formed acetal 5; separation
by recrystallization or chromatography of the four dia-
stereomers of 5 is impractical. However, if the newly
formed acetal carbon could be stereospecifically con-
trolled, alkenyl ethers could prove to be useful chiral
resolving agents, since the protection/deprotection
reactions often proceed in excellent yields and under
mild acidic conditions.4
However, such routes are not available in the resolution
of alcohols, and therefore alcohols (e.g., 1) are often
derivatized with an optically active acyl compound (e.g.,
2) to prepare a diastereomeric mixture of esters (e.g., 3),
R3
O
R3
R4
CO2H
R5
R5
R4
R1 R2
R1 R2
R5
R1 R2
4
H
R4
R3
O
R3
R5
2
O
O
OH
1
R4
We have previously reported on the stereospecific
transformation of tetrahydrocyclopenta[b]furan 6 to cis-
hexahydrocyclopenta[b]furan 7 (Scheme 2).5 This ste-
reospecificity was strongly supported by experimental
measurements of their heat of formations; with a
O
5
3
Two
Diastereomers
Four
Diastereomers
Scheme 1.
OR
Keywords: Chiral resolution; Acetal; Thin layer chromatography;
Alkenyl ether.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.12.104
* Corresponding author. Tel./fax: +81-886-337284; e-mail: nem@
ph.tokushima-u.ac.jp
ROH
H+
O
O
7
6
Scheme 2.
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.104

1668
H. Nemoto et al. / Tetrahedron Letters 45 (2004) 1667–1670
OCH3
OCH3
OCH3
O
O
O
O
( )-9
( )-10
OCH3
( )-11
OCH3
O
O
O
OH
( )-8
( )-12
( )-13
Scheme 4.
Scheme 3.
value since the 2-hexyl moiety has neither p-orbital nor
polar groups, which were presumably essential for effi-
cient separation.1 To further determine whether simi-
larly efficient separation can be obtained from other
2-alkanols, we undertook a TLC study of a series of 14
and 15. Distinctive features of the chemical shifts of 14
and 15 were also noted, and as shown in Table 1, the
following relationships were observed: (1) the longer
the carbon chain length, the greater the DRf value, (2)10
the singlet peak of HCPh2 of 14 always appears in lower
field than the corresponding peak of 15 does in 1H
NMR, and (3)10 peak of HCPh2 of 14 always appears in
higher field than the corresponding peak of 15 does in
13C NMR. It is important to note that the HCPh2 and
HCPh2 NMR signals appeared away from other
potentially interfering peaks, thus providing a facile
method to observe the differences.11
difference of 6.21 kcal/mol, cis-[3.3.0]bicyclooctane was
more stable than the corresponding trans-isomer.6
Herein, we report on an efficient chiral resolution of
2-alkanols using a novel alkenyl ether derivative of tet-
rahydrocyclopenta[b]furan 8. The synthesis of racemic
( )-8 from ( )-95 is shown in Scheme 3. Acetal ( )-9 was
refluxed in benzene in the presence of a catalytic amount
7
of PdCl2(C6H5CN)2 to afford corresponding disubsti-
tuted olefin 10 in 80% isolated yield. Alkene 10 was then
treated with ozone, followed by the addition of dimethyl
sulfide to yield the corresponding aldehyde, which was
subsequently used without further purification. 1,2-
Addition of phenylmagnesium bromide to the aldehyde,
followed by oxidation of the resulting secondary alcohol
using pyridinium dichromate, afforded ketone 11 in 45%
overall yield from 9. An addition reaction between
phenylmagnesium bromide and ketone 11 afforded tert-
alcohol 12 in 79% yield, which was treated with lithium
metal in ammonia to yield diphenylmethane derivative
( )-13 in 78% yield. Acetal ( )-13 was transformed to
alkenyl ether ( )-8 in 82% yield using similar reaction
conditions as for compound 6.5
Since DRf between ( )-14c and ( )-15c are large enough,
and (R)-2-octanol is commercially available, it is obvious
2R-octanol
(-)-14c + (+)-15c
( )-8
94% Yield
Consequently, using newly synthesized ( )-8, we
embarked upon studies of the protection reactions of
2-alkanols (Scheme 4). Typically, the reactions were
carried out in dichloromethane at room temperature,
and in the presence of a catalytic amount of pyridinium
p-toluenesulfonate (PPTS). During the silica gel thin
layer chromatography (TLC)8 identification procedures
using hexane/toluene9 (3:2) as the eluent, DRf value of
0.1 between 14c and 15c (obtained from 2-octanol) was
observed. We were surprised at the relatively large DRf
O
O
(-)-8
(+)-8
Scheme 5.
Table 1. DRf values and the differences of typical distinctive feature of chemical shift between 14 and 15
Acetals
na
DRf
Eluentb
1H NMRc (14/15)
13C NMRd (14/15)
14a/15a
14b/15b
14c/15c
14d/15d
14e/15e
14f/15f
14g/15g
13
9
0.153
0.147
0.099
0.091
0.082
0.045
0.000
120/100
125/100
150/100
175/100
200/100
200/100
200/100
4.57/4.55
4.57/4.55
4.57/4.55
4.57/4.55
4.57/4.55
4.57/4.55
NDe
69.4/70.6
69.3/70.6
69.3/70.6
69.4/70.6
69.3/70.6
69.1/70.4
NDe
6
5
4
3
2
a n of R1 ¼ CnH2nþ1
.
b Eluent ¼ hexane/toluene.
c Chemical shift of HCPh2.
d Chemical shift of HCPh2.
e Not determined.

H. Nemoto et al. / Tetrahedron Letters 45 (2004) 1667–1670
1669
Figure 1.
that ( )-8 can be practically resolved by (R)-2-octa-
nol. Thus we prepared (+)-8 and ())-8 as shown in
Scheme 5. The reaction of ( )-8 and (R)-2-octanol yiel-
the novel chiral resolving agent 8, as well as the factor
responsible for the highly efficient separation.
ded a diastereomeric mixture of ())-14c (½aꢀ25 )153°) and
D
25
D
molar ratio, which were easily separated using silica gel
(+)-15c (½aꢀ +119°) in 94% combined yield with 1:1
Supplementary material
column chromatography. Transformation of ())-14c was
carried out in methanol in the presence of a catalytic
amount of PPTS in to yield ())-13 (½aꢀ )208° (c 0.80,
1
IR, H NMR, 13C NMR, HRMS data or elementary
analyses of all compounds, and X-ray analysis of 16 are
available.
25
D
CHCl3)) in 82% yield, along with the quantitative
recovery of (R)-2-octanol. Transformation of acetal ())-
25
13 to ())-8 (½aꢀ )142° (c 0.138, benzene)) was carried
25
D
out in the same manner as ( )-13 to ( )-8. Similarly, (+)-
8 (½aꢀ +142° (c 0.138, benzene)) was obtained from (+)-
Acknowledgements
D
15c.
We thank Ms. Hiroko Takao, Dr. Hiroshi Imagawa,
Professor Takumichi Sugihara, and Professor Mugio
Nishizawa in Tokushima Bunri University for the
measurement of X-ray of 16. We are grateful to Pro-
fessor Takenori Kusumi of the University of Tokushima
for helpful suggestions and discussions. This work was
in part supported by research grants from Nippon Zeon
Co. Ltd, and Faculty of Pharmaceutical Sciences, The
University of Tokushima.
The absolute configuration at the cis-junction of the
tetrahydrocyclopenta[b]furan skeleton was determined
using X-ray analysis of 16, which was synthesized from
(+)-15c and cholestanol12 (Fig. 1). The results proved
that (+)-8 and ())-8 correspond to the (S)- and (R)-
configurations, respectively. Using R-())-8, TLC of the
(R)-2-alkanol derivatives was reproducibly observed
higher than the (S)-2-alkanol derivatives.
All the acetals that are described herein were shown to be
adequately stable under conditions of silica gel column
chromatography. The protection/deprotection reactions
of 2-alkanol adducts of 8 proceeded in excellent yields
under mild acidic conditions. The stability under silica
gel column chromatographic conditions and mildness of
the protection/deprotection reactions were identical to
those of ethyl vinyl ether or dihydrofuran,13 both of
which have often been used in organic synthesis.4
References and notes
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H. Nemoto et al. / Tetrahedron Letters 45 (2004) 1667–1670
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eluent systems, such as hexane/ether, hexane/ethyl acetate,
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ever, since these solvents resulted identical Rf values for