Synthesis of C2-symmetric chiral crown ethers by lipase-catalyzed reactions

Article abstract of DOI:10.1016/j.tet.2011.09.119

Kinetic resolution of a racemic mixture of C₂-symmetric 18-crown-6 diols (rac-1a) and 15-crown-5 diol (rac-1c) was achieved by lipase-catalyzed acetylation. The enantiomeric excess of the chiral crown diols (95% ee and 82% ee) was determined by ¹H NMR spectroscopy, using (R)-(+)-1-(1-naphthyl)ethylammonium hydrochloride as a shift reagent. The C ₂-symmetric chiral 15-crown-5 diol (>95% ee) was also obtained by kinetic resolution of the racemic diacetate (rac-2c) using lipase-catalyzed solvolysis.

Full text of DOI:10.1016/j.tet.2011.09.119

Tetrahedron 67 (2011) 9298e9304
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Tetrahedron
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Synthesis of C2-symmetric chiral crown ethers by lipase-catalyzed reactions
Misako Nakamura, Takuya Taniguchi, Naohisa Ishida, Keishi Hayashi, Masahiro Muraoka,
*
Yohji Nakatsuji
Department of Applied Chemistry, Faculty of Engineering, Osaka Institute of Technology, 5-16-1 Omiya, Asahi-ku, Osaka 535-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 August 2011
Received in revised form 26 September 2011
Accepted 29 September 2011
Available online 5 October 2011
Kinetic resolution of a racemic mixture of C2-symmetric 18-crown-6 diols (rac-1a) and 15-crown-5 diol
(rac-1c) was achieved by lipase-catalyzed acetylation. The enantiomeric excess of the chiral crown diols
(95% ee and 82% ee) was determined by 1H NMR spectroscopy, using (R)-(þ)-1-(1-naphthyl)ethyl-
ammonium hydrochloride as a shift reagent. The C2-symmetric chiral 15-crown-5 diol (>95% ee) was
also obtained by kinetic resolution of the racemic diacetate (rac-2c) using lipase-catalyzed solvolysis.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Chiral crown ethers
Lipase-catalyzed reaction
Enantiomeric excess
Absolute configuration
1. Introduction
(R,R)-1b and the corresponding 15-crown-5 ethers, for developing
novel chiral recognition host molecules. From this point of view, we
Over the last three decades, chiral crown ethers have been well
established as useful and convenient host compounds for the
separation of enantiomers,1 enantiomeric sensing2 and enantiose-
lective catalysis.2a,3 Further research continues on various chiral
crown ether derivatives with high complexation abilities and se-
lectivity towards guest molecules.1d,4 With respect to the molecular
design of C-pivot lariat ethers,5 we previously prepared a chiral
crown ether containing the C-pivot methyl group, (2R,12R)-2,12-
bis(hydroxymethyl)-2,12-dimethyl-18-crown-6 [(R,R)-1b], and de-
termined its absolute configuration by X-ray anomalous dispersion
analysis of a complex of the derivative.6 Since (R,R)-1b possesses
two reactive groups on the sidearms, it is possible to introduce
further functionalization in pursuit of higher enantioselectivity.
Recently, the introduction of aromatic sidearms into (R,R)-1b
bearing a C-pivot methyl group was found to be a useful strategy for
the design of novel chiral solvating reagents towards primary am-
monium salts. The aromatic sidearm, with restricted movement
due to the methyl group on the C-pivot carbon atom, should affect
its enantiomeric discrimination by the combination of steric and
electronic factors.7 It is therefore of interest to provide a variety of
C2-symmetric chiral crown ethers having two reactive hydrox-
ymethyl groups on the sidearms, such as positional isomers of
describe the synthesis of chiral 2,9-bis(hydroxymethyl)-2,9-
dimethyl-18-crown-6 (1a) and 2,9-bis(hydroxymethyl)-2,9-
dimethyl-15-crown-5 (1c) by lipase-catalyzed reactions and the
determinations of their absolute configurations by comparison
with the corresponding authentic samples synthesized from a chi-
ral subunit, [(4S)-2,2,4-trimethyl-1,3-dioxolane-4-yl]methanol.8
2. Results and discussion
2.1. Synthesis of racemic mixture of 18-crown-6 derivative
The racemic mixture of 18-crown-6 derivative rac-1a was syn-
thesized as shown in Scheme 1. Compound 5 was prepared
according to the previously reported method.9 Compound 5 was
reacted with p-toluenesulfonyl chloride under basic conditions to
give the corresponding ditosylate 6. The Kþ-template reaction of
the conjugate base of ethylene glycol with 6 resulted in the for-
mation of the crown ether 3a in 41% yield. The cis and trans isomers
of compound 3a were separated by silica gel column chromatog-
raphy using a mixture of ethyl acetate and hexane as the eluent. The
trans isomer, a racemic mixture of rac-3a, was treated with po-
tassium acetate in DMSO at 100 ꢀC for 100 h to afford the diacetate
rac-2a in 75% yield. The crown diol rac-1a was prepared by hy-
drolysis of rac-2a in EtOH/H2O in the presence of sodium carbonate
in 100% yield.5d,6 All structures were determined by 1H and 13C
NMR spectroscopy, mass spectrometry and elemental analysis.
* Corresponding author. Tel.: þ81 6 6954 4275; fax: þ81 6 6957 2135; e-mail
address: nakatsuji@chem.oit.ac.jp (Y. Nakatsuji).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.119

M. Nakamura et al. / Tetrahedron 67 (2011) 9298e9304
9299
l
l
l
l
l
Scheme 1. Synthesis of a racemic mixture of 18-crown-6 derivative (rac-1a).
2.2. Synthesis of racemic mixture of 15-crown-5 derivative
The racemic mixtures of 15-crown-5 derivatives rac-1c and rac-
2c were synthesized as shown in Scheme 2. Compound 3c was
obtained by an intramolecular cyclization reaction of the penta-
ethylene glycol derivative, which was prepared by a bromoalkox-
ylation reaction of ethylene glycol bis(2-methylallyl) ether with
ethylene glycol by using benzenesulfonyl chloride under basic
conditions. The cis and trans isomers of 3c were separated by silica
gel column chromatography using a mixture of ethyl acetate and
hexane as eluent.9 The trans isomer, a racemic mixture of rac-3c,
was treated with potassium acetate in DMSO at 100 ꢀC for 96 h to
afford the diacetate rac-2c in 77% yield. The crown diol rac-1c was
obtained by hydrolysis of rac-2c in EtOH/H2O in the presence of
sodium carbonate in 100% yield.5d,6 All structures were determined
by 1H and 13C NMR spectroscopy, mass spectrometry and elemental
analysis.
Scheme 3. Lipase-catalyzed acetylation of rac-1a and rac-1c.
products were obtained after 83 h and 6 days, respectively. Thus,
acetylation of the racemic diol rac-1c with isopropenyl acetate was
carried out in isopropyl ether/THF¼9/1 at 36 ꢀC by using lipase QLM
from Alcaligenes sp. as a catalyst. The reaction was stopped after
6.5 h. The diacetate 2c was isolated by silica gel column
Scheme 2. Synthesis of a racemic mixture of 15-crown-5 derivative (rac-1c).
2.3. Optical resolution of racemic mixture of C2-symmetric
crown diol by lipase-catalyzed acetylation
Kinetic
resolution
of
trans-2,9-bis(hydroxymethyl)-2,9-
dimethyl-18-crown-6 (rac-1a) and trans-2,9-bis(hydroxymethyl)-
2,9-dimethyl-15-crown-5 (rac-1c) was attempted using lipase-
catalyzed acetylation. Acetylation of the racemic diol rac-1a with
isopropenyl acetate was carried out in isopropyl ether at 28 ꢀC by
using lipase QLM from Alcaligenes sp. as a catalyst. The reaction was
monitored by HPLC and was stopped when the HPLC yield of the
diacetate 2a reached 35%. The diacetate 2a was isolated by silica gel
column chromatography (hexane/ethyl acetate¼70/30) in 21%
yield. The diol 1a was obtained by hydrolysis of 2a. The enantio-
meric excess (95% ee) was determined by 1H NMR spectroscopy,
using (R)-(þ)-(1-naphthyl)ethylammonium hydrochloride10 [(R)-
NpEtCl] as a shift reagent (Scheme 3 and Fig. 1).
Acetylation of racemic 15-crown-5 diol rac-1c with isopropenyl
acetate was successfully catalyzed by lipase QLM, in isopropyl ether
containing 10 vol % tetrahydrofuran (THF). In this case, the addition
of THF was necessary for dissolution of rac-1c. In a mixed solvent of
isopropyl ether and THF (50/50) and THF alone, however, no
1
Fig. 1. Partial H NMR spectra (300 MHz, CDCl3, 20 ꢀC) of (a) rac-1a (44.2 mM), (b)
mixture of rac-1a (44.2 mM) and (R)-NpEtCl (44.2 mM) and (c) mixture of chiral diol
1a and (R)-NpEtCl (44.2 mM).

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M. Nakamura et al. / Tetrahedron 67 (2011) 9298e9304
chromatography (hexane/ethyl acetate¼80/20) in 14% yield. The
diol 1c was obtained by hydrolysis of 2c. As shown in Table 1 (entry
1), the enantiomeric excess (82% ee) was determined by 1H NMR
spectroscopy, using (R)-NpEtCl as a shift reagent (Scheme 3 and
Fig. 2). The results of the optical resolution of 15-crown-5 diol rac-
1c using various lipase catalysts are summarized in Table 1.
Table 1
Scheme 4. Lipase QLM-catalyzed solvolysis of rac-2c and hydrolysis of 2c.
Lipase-catalyzed acetylation of 1c
Entry no. Reaction conditions
Lipase Reaction Isolated Enantiomeric
time/h yield/% excess/% ee
Table 2
Lipase QLM-catalyzed solvolysis reaction of rac-2c
1
2
3
4
5
i-Pr2O/THF¼9:1, 36 ꢀ
i-Pr2O/THF¼9:1, 36 ꢀ
i-Pr2O/THF¼9:1, 36 ꢀ
i-Pr2O/THF¼9:1, 36 ꢀ
i-Pr2O/THF¼9:1, 25 ꢀ
C
C
C
C
C
QLMa 6.5
14
16
d
82
46
d
PLa
OFb
TLc
10.5
nrd
4
Entry no.
Reaction conditions
Reaction
Isolated
yielda/%
Enantiomeric
excess/% ee
time/days
16
22
57
77
6
7
8
9
EtOH, 45 ꢀ
C
8
7
11
6
28
21
21
8
50
75
75
QLMa 22
EtOH, 45 ꢀC
a
b
c
EtOH, 37 ꢀC
EtOH/H2O¼9:1, 36 ꢀ
Alcaligenes sp.
Candida cylindracea.
Pseudomonas stutzeri.
No reaction.
C
>95
a
Entry 6: diol; entries 7e9: diacetate (recovered).
d
recovered after reaction. The solvolysis reaction of rac-2c with
ethanol was carried out in hexane at 45 ꢀC for 5 days and then the
unreacted diacetate was recovered. The enantiomeric excess was
determined to be 75% ee (entry 7). When the reaction temperature
was lowered from 45 ꢀC to 37 ꢀC, the reaction time increased, but
the % ee was not improved (entries 7 and 8). On the other hand, the
addition of water to the reaction system dramatically increased the
% ee of 1c (entry 9). The solvolysis of rac-2c with a mixture of
ethanol and water (9:1) in hexane was performed at 36 ꢀC for 6
days. Compound 1c was obtained by hydrolysis of 2c recovered
after reaction and the enantiomeric excess was determined to be
>95% ee (Fig. 3, entry 9 of Table 2). This result strongly suggested
that water played an important role11 in the solvolysis reaction
using lipase QLM as the catalyst. The existence of the water accel-
erate conversion of diacetate by alcoholysis and hydrolysis. This
might be the reason to get the product with very high % ee. In any
case, the % ee obtained by this solvolysis reaction is acceptable for
further applications.
1
Fig. 2. Partial H NMR spectra (300 MHz, CDCl3, 20 ꢀC) of (a) rac-1c (46.3 mM), (b)
mixture of rac-1c (46.3 mM) and (R)-NpEtCl (46.3 mM) and (c) mixture of chiral diol 1c
(entry 1 in Table 1) and (R)-NpEtCl (46.3 mM).
When lipase PL was used as the catalyst, a rather low enantio-
selectivity was observed in comparison with the case of lipase QLM
(entry 2). In the case of lipase OF, no products were obtained after
6.5 h (entry 3). The enantiomeric excess of chiral diol 1c was 57% ee
when using lipase TL (entry 4). Therefore, lipase QLM was adopted
as the catalyst in the kinetic resolution of racemic crown diol rac-
1c. When the reaction was carried out at 25 ꢀC, the enantiomeric
excess of 1c was 77% ee (entry 5).
2.4. Optical resolution of racemic mixture of C2-symmetric
15-crown-5 diacetate by lipase QLM-catalyzed solvolysis
The 82% ee of chiral diol 1c obtained by lipase-catalyzed acet-
ylation was considered to be insufficient for further application of
this reactive crown ether to the design of new chiral host mole-
cules. Accordingly, to improve the % ee of 1c, lipase-catalyzed sol-
volysis of the corresponding diacetate rac-2c with ethanol was
examined in hexane (Scheme 4). The results are summarized in
Table 2.
The lipase QLM-catalyzed solvolysis reaction of rac-2c with
ethanol was carried out in hexane at 45 ꢀC for 8 days. Then com-
pound 1c was isolated and the enantiomeric excess (50% ee) of 1c
was determined by 1H NMR spectroscopy (entry 6). Since the
resulting optical purity of the diol was disappointing, we changed
the target molecule from the diol to the unreacted diacetate
1
Fig. 3. Partial H NMR spectra (300 MHz, CDCl3, 20 ꢀC) of (a) rac-1c (46.3 mM), (b)
mixture of rac-1c (46.3 mM) and (R)-NpEtCl (46.3 mM) and (c) mixture of chiral diol 1c
(entry 9 in Table 2) and (R)-NpEtCl (46.3 mM).
2.5. Determination of absolute configuration using 1H NMR
spectroscopy
2.5.1. Absolute configuration of chiral 18-crown-6 diol. To determine
the absolute configuration of chiral 18-crown-6 diol 1a obtained in
this work, an authentic sample of (R,R)-1a was prepared according
to previously reported methods.8 The 1H NMR chemical shift of the

M. Nakamura et al. / Tetrahedron 67 (2011) 9298e9304
9301
methyl proton signals was found to be in coincidence with that of
the authentic sample, using (R)-NpEtCl as a shift reagent. The ab-
solution configuration of 1a was thus determined to be (R,R)
(Fig. 4).
solvolysis reaction of the corresponding diacetate rac-2c with
a mixture of ethanol and water in hexane. C2-symmetric chiral 15-
crown-5 diol 1c (>95% ee) was obtained by hydrolysis of the
unreacted diacetate recovered after reaction. The absolute con-
figuration of 1a was determined to be (R,R) based on agreement of
the 1H NMR spectrum with that of the authentic (R,R) isomer. The
absolute configuration of chiral 1c was determined to be (S,S) by
comparison with the authentic (R,R) isomer newly prepared in
this work.
4. Experimental section
4.1. General
Lipase QLM was purchased from Meito Sangyo Co. and used
without further purification. 1H NMR spectra at 300 MHz and 13C
NMR spectra at 75 MHz were recorded with a Varian Mercury NMR
spectrometer using tetramethylsilane as an internal standard. Mass
spectra were measured on a JEOL JMS-DX-303 mass spectrometer.
Measurements of the optical rotations were done in a DIP-370
digital polarimeter. Elemental analyses were carried out with
a Yanaco CHN-Corder MT-5 analyzer.
1
Fig. 4. Partial H NMR spectra (300 MHz, CDCl3, 20 ꢀC) of (a) rac-1a (44.2 mM), (b)
mixture of rac-1a (44.2 mM) and (R)-NpEtCl (44.2 mM) and (c) mixture of chiral diol
(R,R)-1a and (R)-NpEtCl (44.2 mM).
4.2. Synthesis of racemic mixture of 18-crown-6 derivative
(rac-1a)
2.5.2. Absolute configuration of chiral 15-crown-5 diol. In the case of
15-crown-5 diol, an authentic sample of (R,R)-1c was newly pre-
pared according to Scheme 5. Compound (R,R)-13 was prepared
The
crude
4,11-bis(bromomethyl)-4,11-dimethyl-3,6,9,12-
tetraoxatetradecan-1,14-diol (5) was prepared according to the
previously reported method.9
from
a chiral subunit of (S)-2,2,4-trimethyl-1,3-dioxolane-4-
methanol (S)-7.8 The Naþ-template cyclization reaction of the diol
(R,R)-13 with diethylene glycol ditosylate under basic conditions
afforded the crown ether (R,R)-14 in 6% yield. (R,R)-1c was obtained
in 72% yield by hydrogenation of (R,R)-14. The chemical shift of the
methyl 1H NMR signals of 1c coincided with that of the (S,S) isomer,
using (R)-NpEtCl as a shift reagent. The absolute configuration of 1c
obtained with lipase-catalyzed solvolysis was determined to
be (S,S).
4.2.1. 4,11-Bis(bromomethyl)-4,11-dimethyl-1,14-bis(tosyloxymethyl)-
3,6,9,12-tetraoxatetradecane(6). To a solution of 5 (90.2 g, 0.199 mol)
in dioxane (340 mL) was added NaOH aq (96% purity, 18.7 g,
0.449 mol, H2O; 41 mL), and a solution of p-toluenesulfonyl chloride
(78.5 g, 0.412 mol) in dioxane (235 mL) was added dropwise at
room temperature. The resulting mixture was stirred at room
temperature for 20 h. After water (100 mL) was added to the solu-
Scheme 5. Synthesis of the chiral crown ether (R,R)-1c.
3. Conclusion
tion, it was then extracted with dichloromethane (400 mLꢁ2). The
combined organic layer was dried over MgSO4 and the dichloro-
methane was evaporated off. The crude product was purified by
chromatography over silica gel (toluene/dioxane¼100/0 to 90/10) to
give 6 as a slightly viscous liquid (55.9 g, 35%). 1H NMR (300 MHz,
In this study, we have established versatile synthetic routes for
C2-symmetric chiral crown diols. The chiral 18-crown-6 diol 1a
was obtained in 95% ee by optical resolution using lipase QLM-
catalyzed acetylation of a racemic mixture of 1a. Chiral 15-
crown-5 diol 1c was obtained in 82% ee by lipase QLM-catalyzed
acetylation. To improve the % ee of chiral diol 1c, optical resolu-
tion of a racemic mixture of 1c was attempted by lipase-catalyzed
CDCl3):
d
1.23 (s, 6H), 2.44 (s, 6H), 3.38 (d, 2H, J¼9.9 Hz), 3.41 (s, 4H),
3.50 (d, 2H, J¼9.8 Hz), 3.58 (s, 4H), 3.68 (t, 4H, J¼5.6 Hz), 4.12 (t, 4H,
J¼5.3 Hz), 7.34 (d, 4H, J¼8.6 Hz), 7.80 (d, 4H, J¼8.4 Hz); 13C NMR
(75 MHz, CDCl3):
d 19.8, 21.6, 36.7, 60.5, 69.4, 70.8, 74.0, 76.1, 128.0,

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M. Nakamura et al. / Tetrahedron 67 (2011) 9298e9304
129.8, 132.9, 144.7; HRMS (FAB) calcd for C28H40Br2O10S2Na:
silica gel (ethyl acetate) to give rac-2c as a slightly yellow viscous
781.0327 ([MþNa]þ). Found: 781.0322 ([MþNa]þ).
liquid in 77% yield.
1H NMR (300 MHz, CDCl3):
d 1.18 (s, 6H), 2.08 (s, 6H), 3.46e3.73
4.2.2. 2,9-Bis(bromomethyl)-2,9-dimethyl-18-crown-6 (3a). To a sti-
rred suspension of powdered KOH (85% purity, 4.35 g, 65.9 mmol)
in dioxane (100 mL) was added dropwise a mixture of 6 (9.99 g,
13.1 mmol) and ethylene glycol (1.29 g, 20.8 mmol) over a 6.5 h
period at 60 ꢀC. The mixture was stirred for 89 h at 60 ꢀC. The in-
soluble matter was removed by filtration and concentrated in
vacuo. Brine (150 mL) was added and the mixture was extracted
with dichloromethane (150 mLꢁ3). The combined organic layer
was dried over MgSO4 and the dichloromethane was evaporated
off. The crude product was purified by medium pressure chroma-
tography over silica gel (hexane/acetone¼93/7) to give 3a as
a slightly yellow viscous liquid (1.91 g, 30%). 1H NMR (300 MHz,
(m, 16H), 4.12 (dd, 4H, J¼11.3, 6.2 Hz); 13C NMR (75 MHz, CDCl3):
d
18.1, 20.9, 62.4, 67.0, 70.7, 71.0, 73.5, 75.8, 170.8. Anal. Calcd for
C18H32O9: C, 55.09; H, 8.22. Found: C, 54.98; H, 8.21.
4.3.2. trans-2,9-Bis(hydroxymethyl)-2,9-dimethyl-15-crown-5 (rac-
1c). The synthetic procedure was almost the same as that used for
rac-1a. The residue was purified by chromatography over alumina
(CHCl3) to give rac-1c as a slightly viscous liquid in 100% yield. 1H
NMR (300 MHz, CDCl3):
d
1.13 (s, 6H), 2.64 (t, 2H, J¼6.2 Hz),
3.53e3.78 (m, 20H); 13C NMR (75 MHz, CDCl3):
d
17.4, 61.8, 67.0,
70.5, 70.8, 75.0, 76.5. Anal. Calcd for C14H28O7: C, 54.53; H, 9.15.
Found: C, 54.53; H, 9.33.
CDCl3):
CDCl3):
d
1.29 (s, 6H), 3.41e3.75 (m, 24H); 13C NMR (75 MHz,
19.6 (trans isomer),19.7 (cis isomer), 37.0 (cis isomer), 37.1
d
4.4. Synthesis of chiral 15-crown-5 ether derivative [(R,R)-1c]
(trans isomer), 62.5, 70.6, 70.8, 71.4, 74.1 (trans isomer), 74.2 (cis
isomer), 76.2. Anal. Calcd for C16H30O6Br2: C, 40.19; H, 6.32. Found:
C, 39.79; H, 6.63.
(2R,11R)-4,11-Dimethyl-1,14-diphenyl-2,6,9,13-
tetraoxatetradecane-4,11-diol [(R,R)-13] was prepared according to
the previously reported method.8
4.2.3. trans-2,9-Bis(bromomethyl)-2,9-dimethyl-18-crown-6
(rac-
3a). This product was a mixture of the cis and trans isomers of 2,9-
bis(bromomethyl)-2,9-dimethyl-18-crown-6 (3a; 9.58 g, 20.0 mmol).
The two stereo isomers were separated by medium pressure chro-
matography over silica gel (hexane/ethyl acetate¼30/70) to give rac-
3a as a slightly viscous liquid (3.44 g, 36%). The trans isomer eluted
4.4.1. (2R,9R)-2,9-bis(benzyloxymethyl)-2,9-dimethyl-15-crown-5
[(R,R)-14]. To
a suspension of NaH (60% in oil, 423 mg,
10.5 mmol) in diglyme (10 mL) was added dropwise a solution of
diethylene glycol ditosylate (1.15 g, 2.52 mmol) and (R,R)-13
(0.880 g, 2.10 mmol) in diglyme (50 mL) and the resulting mix-
ture was stirred for 70 h at 100 ꢀC. After cooling to room tem-
perature, a small portion of MeOH was added to the mixture in
order to deactivate the excess NaH and the mixture was filtered
and concentrated in vacuo. The residue was purified by chro-
matography over silica gel (toluene/ethyl acetate¼95/5e1/1) to
give (R,R)-14 as a slightly yellow viscous liquid (65 mg, 6%). 1H
before the cis isomer. 1H NMR (300 MHz, CDCl3):
3.41e3.75 (m, 24H); 13C NMR (75 MHz, CDCl3):
d
1.29 (s, 6H),
d
19.6, 37.1, 62.6, 70.6,
70.8, 71.4, 74.1, 76.2. Anal. Calcd for C16H30O6Br2: C, 40.19; H, 6.32.
Found: C, 40.12; H, 6.27.
4.2.4. trans-2,9-Bis(acetoxymethyl)-2,9-dimethyl-18-crown-6 (rac-
2a). To a solution of rac-3a (3.76 g, 7.86 mmol) in DMSO (10 mL)
was added potassium acetate (6.20 g, 63.2 mmol) at room tem-
perature. The resulting mixture was stirred for 100 h at 100 ꢀC.
After cooling to room temperature, the mixture was filtered and
concentrated in vacuo. DMSO was removed by distillation in
a Kugelrohr apparatus (45 ꢀC, 0.64 Torr) The crude product was
purified by chromatography over silica gel (ethyl acetate) to give
rac-2a as a slightly yellow viscous liquid (2.58 g, 75%). 1H NMR
NMR (300 MHz, CDCl3):
d 1.19 (s, 6H), 3.35e3.74 (m, 20H), 4.54
(dd, 4H, J¼12.3, 4.1 Hz), 7.24e7.36 (m, 10H); 13C NMR (75 MHz,
CDCl3):
d 18.5, 62.1, 70.6, 70.8, 73.2, 73.3, 73.5, 76.7, 127.4, 127.5,
128.2, 138.6. Anal. Calcd for C28H40O7: C, 68.83; H, 8.25. Found: C,
68.95; H, 8.25.
4.4.2. (2R,9R)-2,9-Bis(hydroxymethyl)-2,9-dimethyl-15-crown-5
[(R,R)-1c]. A suspension of (R,R)-14 (0.117 g, 0.240 mmol) and 20%
Pd/C (40 mg) in a mixed solvent of dioxane/acetic acid (1:1, 8 mL)
was hydrogenated under 5 atm pressure for 220 h at room tem-
perature. The mixture was then filtered and concentrated in
vacuo. The residue was purified by chromatography over alumina
(CHCl3) to give (R,R)-1c as a slightly yellow viscous liquid (53 mg,
(300 MHz, CDCl3):
d 1.19 (s, 6H), 2.08 (s, 6H), 3.48e3.71 (m, 20H),
4.12 (dd, 4H, J¼17.3, 11.4 Hz); 13C NMR (75 MHz, CDCl3):
d 18.1, 21.0,
62.4, 66.3, 70.4, 70.8, 71.4, 74.1, 76.0, 170.8. Anal. Calcd for
C20H36O10: C, 55.03; H, 8.31. Found: C, 54.95; H, 8.31.
4.2.5. trans-2,9-Bis(hydroxymethyl)-2,9-dimethyl-18-crown-6 (rac-
1a). To a solution of rac-2a (2.01 g, 4.60 mmol) in H2O/EtOH (2:1,
15 mL) was added sodium carbonate (0.561 g, 5.29 mmol), followed
by stirring at room temperature for 17 h. The mixture was con-
centrated in vacuo. The residue was purified by chromatography
over alumina (CHCl3) to give rac-1a as a slightly viscous liquid
72%). 1H NMR (300 MHz, CDCl3):
d 1.13 (s, 6H), 2.67 (br s, 2H),
3.49e3.78 (s, 20H); 13C NMR (75 MHz, CDCl3):
d 17.4, 62.0, 67.2,
70.6, 71.0, 75.0, 76.5.
4.5. Optical resolution of C2-symmetric 2,9-bis(hydroxymeth-
yl)-2,9-dimethyl-18-crown-6 using lipase QLM-catalyzed
acetylation
(1.62 g, 100%). 1H NMR (300 MHz, CDCl3):
d 1.12 (s, 6H), 3.09 (t, 2H,
J¼6.0 Hz), 3.49e3.79 (m, 24H); 13C NMR (75 MHz, CDCl3):
d 17.8,
61.5, 65.1, 70.4, 70.8, 71.6, 75.4. Anal. Calcd for C16H32O8: C, 54.53; H,
9.15. Found: C, 54.29; H, 9.24.
4.5.1. Chiral2,9-bis(acetoxymethyl)-2,9-dimethyl-18-crown-6(2a). To
a solution of rac-1a (420 mg, 1.19 mmol) and lipase QLM (40 mg) in
diisopropyl ether (20 mL) was added isopropenyl acetate (7.80 g,
77.9 mmol). The resulting mixture was stirred at 28 ꢀC. The reaction
was monitored by HPLC and stopped when the conversion to acetate
reached 35%. After filtration, the diisopropyl ether was evaporated,
and the residue was purified by chromatography over silica gel
(hexane/ethyl acetate¼70/30) to give 2a as a slightly yellow viscous
4.3. Synthesis of racemic mixture of 15-crown-5 derivative
(rac-1c)
trans-2,9-Bis(bromomethyl)-2,9-dimethyl-15-crown-5 (rac-3c)
was prepared according to the previously reported method.9
4.3.1. trans-2,9-Bis(acetoxymethyl)-2,9-dimethyl-15-crown-5 (rac-
2c). The synthetic procedure was almost the same as that used for
rac-2a. The crude product was purified by chromatography over
liquid (112 mg, 21%). ½a D27
ꢂ
þ10.2 (c 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3):
d 1.19 (s, 6H), 2.08 (s, 6H), 3.48e3.73 (m, 20H), 4.12 (dd, 4H,
J¼17.4, 11.4 Hz); 13C NMR (75 MHz, CDCl3):
d 18.1, 21.0, 62.4, 66.3,

M. Nakamura et al. / Tetrahedron 67 (2011) 9298e9304
9303
70.7, 70.8, 71.4, 74.1, 76.0, 170.8; HRMS (FAB) calcd for C20H36O12
:
stirred at 36 ꢀC. The reaction was stopped at 4 h. After filtration, the
diisopropyl ether and THF were evaporated, and the residue was
purified by medium pressure chromatography over ODS (MeOH/
H2O¼1/1) to give 2c as a slightly yellow viscous liquid (103 mg,16%).
437.2387 ([MþH]þ). Found: 437.2409 ([MþH]þ).
4.5.2. Chiral 2,9-bis(hydroxymethyl)-2,9-dimethyl-18-crown-6 (1a).
The synthesis procedure was almost the same as that used for rac-1a.
The residue was purified by chromatography over alumina (CHCl3) to
give 1a as a slightly viscous liquid in 100% yield. The enantiomeric
excess (95% ee) was determined by 1H NMR spectroscopy, using (R)-
(þ)-(1-naphthyl)ethylammonium hydrochloride [(R)-NpEtCl] as
4.6.7. Chiral 2,9-bis(hydroxymethyl)-2,9-dimethyl-15-crown-5 (1c)
(entry 4). The synthetic procedure was almost the same as that
used for rac-1a. The residue was purified by chromatography over
alumina (CHCl3) to give 1c as a slightly viscous liquid in 76% yield.
The enantiomeric excess (57% ee) was determined by 1H NMR
spectroscopy, using (R)-NpEtCl as a shift reagent.
a shift reagent. ½a D27
ꢂ
þ3.67 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3):
d
1.12 (s, 6H), 3.10 (t, 2H, J¼6.0 Hz), 3.49e3.77 (m, 24H); 13C NMR
(300 MHz, CDCl3):
d
17.8, 61.6, 65.1, 70.5, 70.8, 71.6, 75.5.
4.6.8. Chiral 2,9-bis(acetoxymethyl)-2,9-dimethyl-15-crown-5 (2c)
(entry 5). To a solution of rac-1c (510 mg,1.65 mmol) and lipase QLM
(114 mg) in diisopropyl ether (36 mL) and THF (4 mL) was added
isopropenyl acetate (11.4 mL, 0.105 mmol). The resulting mixture
was stirred at 25 ꢀC. The reactionwas stopped at 22 h. After filtration,
the diisopropyl ether and THF were evaporated, and the residue was
purified by medium pressure chromatography over ODS (MeOH/
H2O¼1/1) to give 2c as a slightly yellow viscous liquid (139 mg, 22%).
4.6. Optical resolution of C2-symmetric 2,9-bis(hydroxymet-
hyl)-2,9-dimethyl-15-crown-5 using lipase-catalyzed
acetylation
4.6.1. Chiral 2,9-bis(acetoxymethyl)-2,9-dimethyl-15-crown-5 (2c)
(entry 1). To a solution of rac-1c (288 mg, 0.936 mmol) and lipase
QLM (55.9 mg) in diisopropyl ether (18 mL) and tetrahydrofuran
(THF, 2 mL) was added isopropenyl acetate (6.54 mL, 60.6 mmol).
The resulting mixture was stirred at 36 ꢀC. The reaction was stopped
at 6.5 h. After filtration, the diisopropyl ether and THF were evapo-
rated, and the residuewas purified bychromatographyover silica gel
(hexane/ethyl acetate¼80/20) to give 2c as a slightly yellow viscous
4.6.9. Chiral 2,9-bis(hydroxymethyl)-2,9-dimethyl-15-crown-5 (1c)
(entry 5). The synthetic procedure was almost the same as that
used for rac-1a. The residue was purified by chromatography over
alumina (CHCl3) to give 1c as a slightly viscous liquid in 100% yield.
The enantiomeric excess (77% ee) was determined by 1H NMR
spectroscopy, using (R)-NpEtCl as a shift reagent.
liquid (52.1 mg, 14%). 1H NMR (300 MHz, CDCl3):
d 1.18 (s, 6H), 2.09
(s, 6H), 3.46e3.73 (m, 16H), 4.12 (dd, 4H, J¼11.3, 6.6 Hz); 13C NMR
(75 MHz, CDCl3): d 18.1, 20.9, 62.4, 66.9, 70.6, 71.0, 73.4, 75.7, 170.8.
Anal. Calcd for C18H32O9: C, 55.09; H, 8.22. Found: C, 54.77; H, 8.26.
4.7. Optical resolution of C2-symmetric 2,9-bis(acetoxymeth-
yl)-2,9-dimethyl-15-crown-5 using lipase QLM-catalyzed
solvolysis
4.6.2. Chiral 2,9-bis(hydroxymethyl)-2,9-dimethyl-15-crown-5 (1c)
(entry 1). The synthetic procedure was almost the same as that used
for rac-1a. The residue was purified by chromatography over alu-
mina (CHCl3) to give 1c as a slightly viscous liquid in 79% yield. The
enantiomeric excess (82% ee) was determined by 1H NMR spec-
troscopy, using (R)-NpEtCl as a shift reagent. 1H NMR (300 MHz,
4.7.1. Chiral 2,9-bis(hydroxymethyl)2,9-dimethyl-15-crown-5 (1c)
(entry 6). To the solution of rac-2c (516 mg, 1.32 mmol) in EtOH
(633 mL, 10.8 mmol) and hexane (25 mL) was added lipase QLM
(523 mg) at 45 ꢀC. The resulting mixture was stirred for 8 days.
After filtration, EtOH and hexane were evaporated, and the residue
was purified by medium pressure chromatography over ODS
(MeCN/H2O¼60/40) to give 1c as slightly viscous liquid (147 mg,
36%). The enantiomeric excess (50% ee) was determined by 1H NMR
spectroscopy, using (R)-NpEtCl as a shift reagent.
CDCl3):
NMR (75 MHz, CDCl3):
d
1.13 (s, 6H), 2.63 (t, 2H, J¼6.4 Hz), 3.53e3.77 (m, 20H); 13
C
d 17.3, 61.8, 67.1, 70.5, 70.8, 74.8, 76.6. Anal.
Calcd for C14H28O7: C, 54.53; H, 9.15. Found: C, 54.63; H, 9.29.
4.6.3. Chiral 2,9-bis(acetoxymethyl)-2,9-dimethyl-15-crown-5 (2c)
(entry 2). To a solution of rac-1c (490 mg, 1.59 mmol) and lipase PL
(635 mg) in diisopropyl ether (45 mL) and THF (5 mL) was added
isopropenyl acetate (4 mL, 37.1 mmol). The resulting mixture was
stirred at 36 ꢀC. The reaction was stopped at 10.5 h. After filtration,
the diisopropyl ether and THF were evaporated, and the residue was
purified by medium pressure chromatography over ODS (MeOH/
H2O¼1/1) to give 2c as a slightly yellowviscous liquid (94.1 mg,16%).
4.7.2. Chiral 2,9-bis(acetoxymethyl)2,9-dimethyl-15-crown-5 (2c)
(entry 7). To the solution of rac-2c (496 mg, 1.26 mmol) in EtOH
(634 mL, 10.9 mmol) and hexane (7 mL) was added lipase QLM
(111 mg) at 45 ꢀC. The resulting mixture was stirred for 7 days. After
filtration, EtOH and hexane were evaporated, and the residue was
purified by chromatography over silica gel (hexane/ethyl
acetate¼80/20) to give unreacted 2c as a slightly yellow viscous
4.6.4. Chiral 2,9-bis(hydroxymethyl)-2,9-dimethyl-15-crown-5 (1c)
(entry 2). The synthetic procedure was almost the same as that
used for rac-1a. The residue was purified by chromatography over
alumina (CHCl3) to give 1c as a slightly viscous liquid in 96% yield.
The enantiomeric excess (46% ee) was determined by 1H NMR
spectroscopy, using (R)-NpEtCl as a shift reagent.
liquid (104 mg, 21%). 1H NMR (300 MHz, CDCl3):
d 1.18 (s, 6H), 2.09
(s, 6H), 3.46e3.73 (m, 16H), 4.12 (dd, 4H, J¼11.3, 6.6 Hz); 13C NMR
(75 MHz, CDCl3): d 18.1, 20.9, 62.4, 66.9, 70.6, 71.0, 73.4, 75.7, 170.8.
Anal. Calcd for C18H32O9: C, 55.09; H, 8.22. Found: C, 54.75; H, 8.59.
4.7.3. Chiral 2,9-bis(hydroxymethyl)-2,9-dimethyl-15-crown-5 (1c)
(entry 7). The synthetic procedure was almost the same as that
used for rac-1a. The residue was purified by chromatography over
alumina (CHCl3) to give 1c as a slightly viscous liquid in 100% yield.
The enantiomeric excess (75% ee) was determined by 1H NMR
4.6.5. Chiral 2,9-bis(acetoxymethyl)-2,9-dimethyl-15-crown-5 (2c)
(entry 3). To a solution of rac-1c (496 mg, 1.61 mmol) and lipase OF
(107 mg) in diisopropyl ether (45 mL) and THF (5 mL) was added iso-
propenyl acetate (4 mL, 37.1 mmol). The resulting mixture was stirred
at 36 ꢀC. The reaction did not progress and was stopped after 6.5 h.
spectroscopy, using (R)-NpEtCl as
(300 MHz, CDCl3): 1.13 (s, 6H), 2.70 (br s, 2H), 3.77e3.73 (m, 20H);
13C NMR (75 MHz, CDCl3):
17.4, 62.0, 67.3, 70.7, 71.0, 75.2, 76.7.
a
shift reagent. 1H NMR
d
d
4.6.6. Chiral 2,9-bis(acetoxymethyl)-2,9-dimethyl-15-crown-5 (2c)
(entry 4). To a solution of rac-1c (522 mg, 1.69 mmol) and lipase TL
(100 mg) in diisopropyl ether (54 mL) and THF (6 mL) was added
isopropenyl acetate (4.5 mL, 41.8 mmol). The resulting mixture was
Anal. Calcd for C14H28O7: C, 54.53; H, 9.15. Found: C, 54.47; H, 9.28.
4.7.4. Chiral 2,9-bis(acetoxymethyl)2,9-dimethyl-15-crown-5 (2c)
(entry 8). To the solution of rac-2c (211 mg, 0.536 mmol) in EtOH

9304
M. Nakamura et al. / Tetrahedron 67 (2011) 9298e9304
(260
mL, 4.45 mmol) and hexane (5 mL) was added lipase QLM
References and notes
(41 mg) at 37 ꢀC. The resulting mixture was stirred for 11 days. After
filtration, EtOH and hexane were evaporated, and the residue was
purified by chromatography over silica gel (hexane/ethyl
acetate¼80/20) to give unreacted 2c as a slightly yellow viscous
liquid (46 mg, 21%).
1. (a) Sogah, G. D. Y.; Cram, D. J. J. Am. Chem. Soc. 1976, 98, 3038e3041; (b) Sousa,
L. R.; Sogah, G. D. Y.; Hoffman, D. H.; Cram, D. J. J. Am. Chem. Soc. 1978, 100,
4569e4576; (c) Lehn, J.-M.; Simon, J.; Moradpour, A. Helv. Chim. Acta 1978, 61,
2407e2418; (d) Sogah, G. D. Y.; Cram, D. J. J. Am. Chem. Soc. 1979, 101,
3035e3042; (e) Galan, A.; Andreu, D.; Echavarren, A. M.; Prados, P.; Mendoza, J.
D. J. Am. Chem. Soc. 1992, 114, 1511e1512; (f) Zhang, X. X.; Bradshaw, J. S.; Izatt,
R. M. Chem. Rev. 1997, 97, 3113e3361; (g) Hirose, K.; Ogasahara, K.; Nishioka, K.;
Tobe, Y.; Naemura, K. J. Chem. Soc., Perkin Trans. 2 2000, 1984e1993; (h) Hirose,
K.; Yongzhu, J.; Nakamura, T.; Nishioka, R.; Ueshige, T.; Tobe, Y. Chirality 2005,
17, 142e148.
2. (a) Lehn, J.-M. Angew. Chem., Int. Ed. Engl. 1988, 27, 89e112; (b) Tsubaki, K.;
Tanima, D.; Murazzaman, M.; Kusumoto, T.; Fuji, K.; Kawabata, T. J. Org. Chem.
2005, 70, 4609e4616; (c) Tanima, D.; Imamura, Y.; Kawabata, T.; Tsubaki, K. Org.
Biomol. Chem. 2009, 7, 4689e4694.
3. Kellogg, R. M. Angew. Chem., Int. Ed. Engl. 1984, 23, 782e794.
4. (a) Helgeson, R. C.; Koga, K.; Timko, J. M.; Cram, D. J. J. Am. Chem. Soc. 1973,
95, 3021e3023; (b) Curtis, W. D.; Laidler, D. A.; Stoddart, J. F.; Jones, G. H.
J. Chem. Soc., Chem. Commun. 1975, 835e837; (c) Laidler, D. A.; Stoddart, J.
F. J. Chem. Soc., Chem. Commun. 1976, 979e980; (d) Davidson, R. B.;
Bradshaw, J. S.; Jones, B. A.; Dalley, K.; Christensen, J. J.; Izatt, R. M. J. Org.
Chem. 1984, 49, 353e357; (e) Huszthy, P.; Bradshaw, J. S.; Zhu, C. Y.; Izatt,
R. M. J. Org. Chem. 1991, 56, 3330e3336; (f) Naemura, K.; Takeuchi, S.;
Hirose, K.; Tobe, Y.; Kaneda, T.; Sakata, Y. J. Chem. Soc., Perkin Trans. 1 1995,
213e219.
5. (a) Nakatsuji, Y.; Nakamura, T.; Okahara, M.; Dishong, D. M.; Gokel, G. W. J. Org.
Chem. 1983, 48, 1237e1242; (b) Nakatsuji, Y.; Nakamura, T.; Yonetani, M.; Yuya,
H.; Okahara, M. J. Am. Chem. Soc. 1988, 110, 531e538; (c) Nakatsuji, Y.; Kita, K.;
Inoue, H.; Zhang, W.; Kida, T.; Ikeda, I. J. Am. Chem. Soc. 2000,122, 6307e6308; (d)
Nakahara, Y.; Kida, T.; Nakatsuji, Y.; Akashi, M. J. Org. Chem. 2004, 69, 4403e4411.
6. Muraoka, M.; Ueda, A.; Zhang, W.; Kida, T.; Nakatsuji, Y.; Ikeda, I.; Kanehisa, N.;
Kai, Y. Tetrahedron Lett. 1998, 39, 9493e9496.
4.7.5. Chiral 2,9-bis(hydroxymethyl)-2,9-dimethyl-15-crown-5 (1c)
(entry 8). The synthetic procedure was almost the same as that
used for rac-1a. The residue was purified by chromatography over
alumina (CHCl3) to give 1c as a slightly viscous liquid in 100% yield.
The enantiomeric excess (75% ee) was determined by 1H NMR
spectroscopy, using (R)-NpEtCl as a shift reagent.
4.7.6. Chiral 2,9-bis(acetoxymethyl)2,9-dimethyl-15-crown-5 (2c)
(entry 9). To the solution of rac-2c (404 mg, 1.03 mmol) in EtOH
(456 mL, 7.81 mmol), H2O (40 mL, 2.22 mmol) and hexane (14 mL)
was added lipase QLM (82 mg) at 36 ꢀC. The resulting mixture was
stirred for 6 days. After filtration, EtOH and hexane were evapo-
rated, and the residue was purified by chromatography over silica
gel (hexane/ethyl acetate¼80/20) to give unreacted 2c as a slightly
a 26
yellow viscous liquid (32 mg, 8%). ½ ꢂD ꢃ6.06 (c 1.1, CHCl3).
4.7.7. Chiral 2,9-bis(hydroxymethyl)-2,9-dimethyl-15-crown-5 (1c)
(entry 9). The synthetic procedure was almost the same as that used
for rac-1a. The residue was purified bychromatographyoveralumina
(CHCl3) to give 1c as a slightly viscous liquid in 100% yield. The en-
antiomeric excess (>95% ee) was determined by 1H NMR spectros-
7. Nakatsuji, Y.; Nakahara, Y.; Muramatsu, A.; Kida, T.; Akashi, M. Tetrahedron Lett.
2005, 46, 4331e4335.
8. Nakatsuji, Y.; Nakahara, Y.; Nagamiya, K.; Itoh, Y.; Uesugi, K.; Ishida, N.; Mur-
aoka, M.; Kida, T.; Akashi, M. Synthesis 2007, 2973e2978.
9. (a) Nakatsuji, Y.; Mori, T.; Okahara, M. Tetrahedron Lett. 1984, 25, 2171e2174;
(b) Nakatsuji, Y.; Sunagawa, T.; Masuyama, A.; Kida, T.; Ikeda, I. J. Inclusion
Phenom. Mol. Recognit. Chem. 1997, 29, 289e299; (c) Nakatsuji, Y.; Muraoka,
M.; Kajiya, H.; Zhang, W.; Kida, T.; Ikeda, I. Bull. Chem. Soc. Jpn. 2002, 75,
1765e1770.
copy, using (R)-NpEtCl as a shift reagent. ½a D26
þ2.33 (c 1.0, CHCl3).
ꢂ
Acknowledgements
We greatly thank Meito Sangyo Co., Nagoya, for donation of the
lipases PL, OF and TL.
10. (R)-(þ)-(1-naphthyl)ethylammonium hydrochloride [(R)-NpEtCl] was syn-
thesized according to the following method. 1
N hydrochloric acid was
added to the solution of (R)-(þ)-(1-naphthyl)ethylamine in EtOH at room
temperature. The mixture was concentrated in vacuo. The residue salts was
crystallized from MeCN/MeOH mixture. The salt was obtained as a white
solid.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.09.119.
11. (a) Zaks, A.; Klibanov, A. M. Science 1984, 224, 1249e1251; (b) Klibanov, M.
CHEMTECH 1986, 16, 354e359.