A facile and practical method of preparing optically active α-monosubstituted cycloalkanones by thermodynamically controlled deracemization

Article abstract of DOI:10.1016/j.tet.2010.09.085

Racemic 2-monosubstituted cycloalkanones were converted to R-isomers when TADDOLs (e.g., 1a, b) were used as host molecules in alkaline aqueous MeOH. The efficiency of this thermodynamically controlled deracemization was strongly influenced by the mixture ratio of the solvent, H₂O/MeOH. Based on this finding, an improved method of preparing (R)-2-monosubstituted cycloalkanones with higher optical purity was developed. For example, (R)-2-(4-methylbenzyl)cyclohexanone (5) was obtained in 85% yield with 98% ee, when a 1:1 mixture of H₂O/MeOH was used as the solvent in the presence of 1a.

Full text of DOI:10.1016/j.tet.2010.09.085

Tetrahedron 66 (2010) 9450e9455
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A facile and practical method of preparing optically active a-monosubstituted
cycloalkanones by thermodynamically controlled deracemization
*
*
Hiroto Kaku , Aya Nakamaru, Makoto Inai, Takeshi Nishii, Mitsuyo Horikawa, Tetsuto Tsunoda
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2010
Received in revised form 25 September 2010
Accepted 27 September 2010
Available online 1 October 2010
Racemic 2-monosubstituted cycloalkanones were converted to R-isomers when TADDOLs (e.g., 1a, b)
were used as host molecules in alkaline aqueous MeOH. The efficiency of this thermodynamically con-
trolled deracemization was strongly influenced by the mixture ratio of the solvent, H2O/MeOH. Based on
this finding, an improved method of preparing (R)-2-monosubstituted cycloalkanones with higher op-
tical purity was developed. For example, (R)-2-(4-methylbenzyl)cyclohexanone (5) was obtained in 85%
yield with 98% ee, when a 1:1 mixture of H2O/MeOH was used as the solvent in the presence of 1a.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Deracemization
Molecular recognition
Hosteguest chemistry
Inclusion complexation
Optically active cycloalkanones
1. Introduction
a chiral center at the a
-position.8,9 The resolution efficiency (E)10 of
this method, however, cannot exceed 100%.
Optically active
a
-monosubstituted ketones are widely used as
In previous papers, we reported thermodynamically controlled
deracemization11,12 of several cycloalkanones using hosteguest
chemistry in basic suspension media. For example, the use of (2R,3R)-
(ꢀ)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro[5.4]decane
(1a)13 (1.0e2.0 equiv) as a host molecule with alkaline aqueous MeOH
converted racemic 2-benzylcyclohexanone (2) and 2-(2-methoxy-
ethyl)cyclohexanone (3) to the R-isomer in quantitative yield with 74%
ee and 94% ee, respectively (Scheme 1). The E values of deracemization
for (ꢁ)-2 and 3 were increased up to 148% and 180%, respectively.
starting materials in the syntheses of complex molecules, such as
natural products and biologically active compounds. Enantiose-
lective protonation1e3 and alkylation4 of ketones (enolates) and
their derivatives, such as enamines,5 imines,6 and hydrazines,7 are
necessary to obtain such optically active ketones. These methods,
however, require multistep transformations and carefully con-
trolled conditions. In contrast, inclusion complexation can be easily
and successfully used for the optical resolution of ketones bearing
OH OH
1a (1.0 or 2.0 equiv)
NaOH (4 equiv)
Ph
Ph
Ph
Ph
O
O
R
R
O
O
H2O / MeOH = 1 / 1
rt, 2 days
(R)-2 >99%, 74% ee (with 1.0 equiv of 1a)
( )-2 : R = -CH2Ph
(R)-3 99%, 88% ee (with 2.0 equiv of 1a)
( )-3 : R = -CH2CH2OCH3
1a
96%, 94% ee (with 2.0 equiv of 1a in H2O / MeOH = 2 / 1)
Scheme 1. Deracemization of (ꢁ)-2-benzyl- and (ꢁ)-2-(2-methoxyethyl)cyclohexanone.
* Corresponding authors. E-mail addresses: kaku@ph.bunri-u.ac.jp (H. Kaku),
tsunoda@ph.bunri-u.ac.jp (T. Tsunoda).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.085

H. Kaku et al. / Tetrahedron 66 (2010) 9450e9455
9451
We revealed that this unique phenomenon was accomplished
by chiral molecular recognition induced by inclusion complexation.
Furthermore, X-ray analytical studies disclosed the nature of this
chiral molecular recognition process in solid phase in detail.14 Thus,
deracemization could provide a convenient and excellent method
The solvent dependence of the deracemization of (ꢁ)-2 using 1a
is shown in Fig. 1a. When the proportion of water was 10%, 2 was
not recovered from the solid phase because of the high solubility of
2 in the solvent. In 20% water, (R)-2 was obtained in about 50% yield
with 90% ee. Although most of guest molecule 2 was recovered
from the solid phase in more than 50% of water, the optical purity of
2 decreased gradually to 66% ee, suggesting that some of guest
molecule 2 simply adhered to the surface of solid phase (host 1a)
due to the low solubility of oily 2 in the water-enriched solvent.
A somewhat similar phenomenon was observed with the com-
bination of 1a and cycloalkanones 3e9 (Fig. 1beh). Cycloalkanones
2, 3, 5, and 7 were recognized by host 1a with good to excellent ef-
ficiency. In the case of 3, 2 equiv of host 1a was required for dera-
cemization with high efficiency, because a 1:2 inclusion complex
must be formed.11,16 In contrast, the chiral recognition efficiency of 4,
6, and 8 by 1a was only moderate. The introduction of some methyl
groups on the side chain (4 versus 7) and on the aromatic ring (2
versus 5) influenced the molecular recognition process. Efficiency
of preparing optically active a-monosubstituted cyclohexanones.
Although (4R,5R)-(ꢀ)-trans-4,5-bis(hydroxydiphenylmethyl)-2-
phenyl-1,3-dioxolane (1b)13 gave better results than 1a for the
deracemization of (ꢁ)-2-allylcyclohexanone (4), efficiency was
maintained at 62% ee (R-isomer) with 96% yield (E value¼119%)
(Scheme 2). To obtain 4 with higherenantiomeric excess, wefocused
on the solubility of 4 in aqueous MeOH as the solvent, and found that
the proportion of water in the aqueous MeOH influenced the optical
purity of the ketone 4. Furthermore, the optical purity of 4 increased
1a or 1b (1.0 equiv)
NaOH (4 equiv)
OH OH
Ph
Ph
O
O
Ph
Ph
was dramatically decreased by the absence of a p-electron system
H2O / MeOH = 1 / 1
rt, 2 days
O
O
H
on the side chain (7 vs8), especially, 9 was notincluded by1a (4 vs 9).
The ring size of cycloalkanones (2 vs 6) also affected the affinity
between the host and guest molecules. Exchanging host molecule 1a
for 1b led to more effective inclusion of (R)-4 into the solid phase
(Fig. 2 versus Fig. 1c). Thus, deracemization was influenced by the
( )-4
(R)-4
Ph
96%, 34% ee (with 1a)
96%, 62% ee (with 1b)
1b
Scheme 2. Deracemization of (ꢁ)-2-allylcyclohexanone.
functionality,
p-electron, and architecture of the a-alkyl side chain,
and the ring size of the cycloalkanones.17
when the recovery of 4 was sacrificed to some extent by filtration.
Eventually, (R)-4 was afforded in 70% yield with 93% ee when a 7:3
mixture of H2O/MeOH was used as the solvent (Scheme 3).15
Based on these findings shown in Figs. 1 and 2, an improved
procedure for deracemization was developed. Deracemization of
1b (1.0 equiv)
NaOH (4 equiv)
H2O / MeOH
(7 / 3)
< filtration >
< filtration >
< SiO2 column >
(R)-4
solid
solid
( )-4
rt, 1 day
H2O / MeOH
(7 / 3)
rt, 2 days
70%, 93% ee
filtrate
filtrate
Scheme 3. Deracemization of (ꢁ)-2-allylcyclohexanone.
Here we describe in detail that deracemization of various
a
-
(ꢁ)-2 using 1a was focused on as an example. In the original
method (Scheme 1), 50% aqueous MeOH was used as a solvent and
the reaction mixture was treated with a saturated NH4Cl aqueous
solution and extracted with ether to satisfactorily recover the entire
2. However, the enantiomer excess of recovered 2 was only 74% ee.
When the same ratio of H2O/MeOH (orange line in Fig. 1a) was
used, 2 was recovered in 95% yield with 80% ee. So, it was presumed
that the recovered 2 in original method was contaminated by ad-
hesion of solute molecule 2, which was not included by the host 1a,
resulting in a 1:1 mixture of racemic isomers. This was why the
optical purity of the recovered 2 remained at 74% ee of the R-isomer,
monosubstituted cycloalkanones is solvent-dependent, as in the
case of 4 with 1b. Moreover, we present a newly developed pro-
cedure that provides a facile and practical method for preparing
optically active a-monosubstituted cycloalkanones.
2. Results and discussion
In the present study, the solid phase was separated from the
liquid phase by filtration after deracemization to precisely evaluate
the efficiency of the molecular recognition process (Scheme 4).
1a or 1b (1.0 equiv), NaOH (4 equiv)
50 mg of ( )-guest
< filtration >
solid
< GLC analysis >
H2O / MeOH, rt, 2 days
(5 mL)
filtrate
Scheme 4. Method for deracemization.
Optical and chemical yields of the guest compound (cycloalkanone)
recovered from the solid phase were determined by gaseliquid
chromatography (GLC) and plotted against the proportion (in %) of
water in aqueous MeOH.
even though 90% ee of (R)-2 was included in the solid phase (green
line in Fig. 1a).
Therefore, a new procedure was developed with the following
considerations: (1) To ensure high optical purity, recovery of 2 is

9452
H. Kaku et al. / Tetrahedron 66 (2010) 9450e9455
Fig. 1. Solvent dependence of chemical and optical yields of 2e9 recovered from the solid phase using 1a.
sacrificed to some extent by filtration. (2) To eliminate adhesion
(vide supra) and further enhance the optical purity of 2, the solid
phase, which is a mixture of 1a and 2 obtained by filtration, is again
suspended again in fresh solvent without a base. That is, the mix-
ture is subjected to optical resolution by inclusion recomplexation
to remove unfavorable enantiomers (S-isomer) of 2 into the sol-
vent. (3) The H2O/MeOH ratio appreciably influences the efficiency
of this new procedure. When the proportion of MeOH is too high,
recovery of 2 decreases. On the other hand, the enantiomeric excess
of 2 decreases when the solvent contains a higher proportion of
water.
A 3:7 mixture of H2O/MeOH (green line in Fig. 1a) was selected
as the solvent for improved deracemization of (ꢁ)-2 with 1a. For
example, the host molecule 1a (5.38 g, 10.6 mmol) was added to

H. Kaku et al. / Tetrahedron 66 (2010) 9450e9455
9453
3. Conclusions
We found that the efficiency of thermodynamically controlled
deracemization was appreciably influenced by the ratio of H2O/
MeOH used as a solvent, which led to the development of an im-
proved method to prepare (R)-2-monosubstituted cycloalkanones
with higher optical purity. Further studies to disclose the principle
of the molecular recognition process and the applicability of the
present method are in progress.
4. Experimental section
4.1. General
Melting points were determined on a Yanaco MP-3 apparatus
and were uncorrected. Infrared (IR) spectra were recorded from ei-
ther neat liquid films or solids in KBr pellets on a JASCO Model FT/IR-
410 spectrophotometer. Proton nuclear magnetic resonance spectra
(1H NMR) were recorded on a Varian Gemini 200 (200 MHz), Varian
Unity 200 (200 MHz), Varian Mercury 300 (300 MHz), or Varian 400
MR(400 MHz)spectrometerin CDCl3. Chemicalshifts werereported
Fig. 2. Solvent dependence of chemical and optical yields of 4 recovered from the solid
phase using 1b.
in parts per million (d) relative to internal Me4Si (0.00 ppm), and
coupling constants are given in hertz. The abbreviations s¼singlet,
d¼doublet, t¼triplet, m¼multiplet, br¼broad were used. 13C NMR
spectra were obtained on a Varian 400 MR (100 MHz) and chemical
shifts were referenced to the residual solvent signal (CDCl3:
a solution of (ꢁ)-2 (2.02 g, 10.7 mmol) in H2O (17.5 mL) and MeOH
(140 mL), then
a 1 M sodium hydroxide aqueous solution
(42.5 mL, 42.5 mmol) was added to the suspension (finally, the
ratio of H2O/MeOH was 3:7). The mixture was stirred at room
temperature for 2 days, and the resulting mixture was filtered and
the residue was washed with H2O/MeOH (3:7, 5 mLꢂ3). The
resulting residue, the solid phase, was then suspended again in
a fresh mixture of H2O/MeOH (3:7, 200 mL) without a base at
ambient temperature for 1 day. After filtration followed by
washing with H2O/MeOH (3:7, 5 mLꢂ3), the residue was sepa-
rated by column chromatography to afford (R)-2 with 93% ee in
72% yield (Scheme 5).
d
76.9 ppm). Mass spectra, including high-resolution mass spectra,
were recorded on a JEOL AX-500 spectrometer.
Optional rotations were measured on a JASCO DIP-1000 polarim-
eter using a 10-cm microcell. Capillary gas chromatographic analyses
were performed on a Shimadzu GC-14A gas chromatograph equipped
with 30 mꢂ0.25 mm fused-silica
a-DEX120 SUPELCO columns. He-
lium was used as the carrier gas and peak area integrations for the
flameionizationdetectorresponsewereuncorrected. AnalyticalHPLC
was performed on a JASCO system consisting of a pump (PU-980) and
1a (1.0 equiv)
NaOH (4 equiv)
H2O / MeOH
(3 / 7)
< filtration >
< filtration >
< SiO2 column >
(R)-2
solid
solid
( )-2
rt, 1 day
H2O / MeOH
(3 / 7)
rt, 2 days
72%, 93% ee
filtrate
filtrate
Scheme 5. Deracemization of (ꢁ)-2 using new method.
Deracemization of (ꢁ)-3e8 was performed similarly using the
new procedure. These results along with those of our previous
studies are summarized in Table 1. In the case of 5, a 1:1 mixture of
H2O/MeOH (see Fig. 1d, green line) was necessary for the reaction
to afford (R)-5 with 98% ee in 85% yield (entry 2). In contrast, 6 was
not adequately recognized by 1a (see Fig.1e), so the deracemization
efficiency remained at only 50% ee (R-isomer) in 78% yield, even
using the new procedure (entry 3).
Compound (R)-7 fitted more effectively than (R)-4 into the chiral
cavity constituted by aggregation of the optically active host mol-
ecule 1a (Fig. 1f vs 1c). Then, (R)-7 was obtained with 96% ee in 96%
yield (entry 5). Applying the new procedure to 8, a hydrogenated
compound of 7, gave only a moderate yield (46%), but provided
excellent optical purity (96% ee). Host molecule 1b was significantly
superior to 1a for the deracemization of (ꢁ)-4 in a 7:3 mixture of
H2O/MeOH to provide the R-isomer with 93% ee in 70% yield (Fig.1c
versus 2, entry 4). Because 3 was recognized effectively by two
equimolar amounts of 1a, the new procedure was not necessary for
deracemization in this case.
a photodiode array detector (UV-970, set at 254 nm) and equipped
with a Daicel CHIRALCEL OJ or AD column. Peak areas were measured
by electronic integration on a Shimadzu C-R7Aplus chromatopac.
In general, reagent grade solvents were used. N,N-Dime-
thylformamide (DMF) was distilled from CaH2 under reduced
pressure. Dichloromethane and triethylamine were distilled from
CaH2 under argon atmosphere. Analytical thin layer chromatogra-
phy (TLC) was performed on precoated silica-gel 60 F-254 plates
(0.2-mm layers) on glass with fluorescent indicator, supplied by E.
Merck. For column chromatography, a Fuji Silysia BW-127ZH
(100e270 mesh) or BW-300 (200e400 mesh) was used.
4.2. Solvent dependence of deracemization (Scheme 4)
In a 5-mL flask, distilled water and 1 M sodium hydroxide
aqueous (4 equiv) were added to a mixture of ketone (50 mg) and
host 1a or 1b in methanol. The resulting mixture was stirred vig-
orously at ambient temperature for 2 days and then filtered. The
obtained white solid was dissolved in ether and dried over MgSO4.

9454
H. Kaku et al. / Tetrahedron 66 (2010) 9450e9455
Table 1
Deracemization of
a
-substituted cycloalkanones
host
NaOH (4 equiv)
< filtration >
< filtration >
H2O / MeOH
rt, 1 day
< SiO2 column >
(R)-guest
( )-guest
solid
solid
H2O / MeOH
rt, 2 days
2-8
filtrate
filtrate
Entry
1
Guest
Host (equiv)
<Previous work>
<Present work>
% Yield (% ee)/(ratio of H2O/MeOH)
% Yield (% ee)/(ratio of H2O/MeOH)
O
1a (1)
1a (1)
100 (74:R)/(1/1)
71 (93:R)/(3/7)
2
O
2
3
96 (82:R)(1/1)
85 (98:R)/(1/1)
78 (50:R)/(1/1)
Me
5
O
1a (1)
100 (36:R)/(1/1)
6
O
4
5
6
1b (1)
1a (1)
1a (1)
96 (62:R)/(1/1)
97 (90:R)/(2/1)
92 (46:R)/(2/1)
70 (93:R)/(7/3)
96 (96:R)/(1/1)
48 (96:R)/(1/1)
4
O
7
O
8
O
OMe
7
1a (2)
96 (94:R)/(2/1)
da
3
a
No experimental results.
This solution was used for analyses. The optical purity of ketone
was determined by GLC using a chiral column (SUPELCO,
4.4. Typical experiment of improved deracemization (Table 1,
entry 2)
a
-
DEX120). To determine the yield of recovered ketone, a straight-
chain hydrocarbon (dodecane or hexadecane) was added as an
internal standard. The optical and chemical yields of the guest
compound recovered from the solid phase were plotted against the
proportion (in %) of water in aqueous MeOH (Figs. 1 and 2).
The host molecule 1a (627.2 mg, 1.24 mmol) was added to the
solution of 5 (250.1 mg, 1.24 mmol) in distilled H2O (11.3 mL) and
MeOH (12.5 mL), then a 4 M sodium hydroxide aqueous solution
(1.24 mL, 4.96 mmol) was added to the suspension (finally, the
ratio of H2O/MeOH was 1:1, green line in Fig. 1d). The resulting
mixture was stirred at room temperature for 2 days. The mixture
was filtered and the residue was washed with the same ratio of
a mixture of H2O/MeOH (1:1, 2 mLꢂ3). The resulting residue, the
solid phase, was suspended again into a fresh mixture of H2O/
MeOH (1:1, 25 mL) at ambient temperature for 1 day. After fil-
tration followed by washing with H2O/MeOH (1:1, 2 mLꢂ3), the
residue was dissolved in ether and subjected to GLC analysis to be
98% ee of (R)-5. Purification of the residue by silica gel column
chromatography (hexane/ether) yielded (R)-5 (212.9 mg, 85%) as
a colorless oil.
4.3. General method for improved deracemization (Table 1)
Distilled water and 1 M sodium hydroxide aqueous (4 equiv)
were added to a suspension of ketone and host 1a or 1b in methanol.
By considering Fig. 1 or 2, the ratio of water/methanol at the level of
the green line was determined. The suspension was stirred at am-
bient temperature for 2 days. The mixture was filtered and the res-
idue was washed with the same ratio of a mixture of H2O/MeOH
(2 mLꢂ3). The resulting residue, the solid phase, was suspended
again into a fresh mixture of H2O/MeOH at ambient temperature for
1 day. After filtration followed by washing with H2O/MeOH
(2 mLꢂ3), the residue was dissolved in ether and subjected to GLC to
afford an enantiomeric excess of ketone. Purification of the residue
by silica gel column chromatography (hexane/ether) yield gave the
ketone as a colorless oil.
4.4.1. (R)-2-Benzylcyclohexanone: (R)-218. Chiral GLC analysis,
tR¼32.7 (R), 33.3 (S) min (SUPERCO,
a
-DEX120, 150 ꢃC).
25
[
a
]
þ28.6 (c 1.17, MeOH) (61% ee). CDCHCl3
[
q
]¼þ1720,
D
D3¼þ0.52 (78% ee). 1H NMR (400 MHz, CDCl3)
d
1.35 (dddd, J¼3.7,
12.1, 12.1, 13.3 Hz, 1H), 1.52e1.63 (m, 1H), 1.63e1.74 (m, 1H), 1.83

H. Kaku et al. / Tetrahedron 66 (2010) 9450e9455
9455
(dddd, J¼1.6, 3.7, 7.2, 11.1 Hz, 1H), 1.98e2.10 (m, 2H), 2.33 (dddd,
J¼1.3, 6.0, 12.7, 13.7 Hz, 1H), 2.41 (dd, J¼8.8, 13.9 Hz, 1H), 2.40e2.47
(m, 1H), 2.50e2.59 (m, 1H), 3.23 (dd, J¼4.9, 13.9 Hz, 1H), 7.13e7.21
4.4.7. (R)-2-Isopentylcyclohexanone: (R)-8. Chiral GLC analysis,
tR¼40.3 (R), 41.4 (S) min (SUPERCO,
-DEX120, 110 ꢃC).
a
20
[a
]
þ14.8 (c 0.997, CHCl3) (46% ee). CDCHCl3
[q]¼þ1323,
D
(m, 3H), 7.24e7.30 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
25.3, 28.2,
D3¼þ0.401 (46% ee). 1H NMR (400 MHz, CDCl3)
d
0.871 (d, J¼6.6 Hz,
33.6, 35.6, 42.4, 52.7, 126.1, 128.5, 129.3, 140.5, 212.8; IR (ATR)
1704.8 (C]O) cmꢀ1; MS (EI) m/z: 188 (Mþ, base peak), 159, 145, 97,
91; HRMS (EI) m/z: (Mþ) calcd for C13H16O, 188.1201; found,
188.1195.
3H), 0.883 (d, J¼6.6 Hz, 3H), 1.10e1.24 (m, 3H), 1.39 (dddd, J¼3.6,
11.2,11.2, 13.2 Hz,1H),1.52 (m,1H), 1.58e1.64 (m, 1H), 1.64e1.72 (m,
1H), 1.72e1.80 (m, 1H), 1.80e1.89 (m, 1H), 1.98e2.06 (m, 1H),
2.07e2.15 (m, 1H), 2.18e2.26 (m, 1H), 2.26e2.33 (m, 1H), 2.39
(dddd, J¼1.4, 4.3, 4.3, 13.3, 1H); 13C NMR (100 MHz, CDCl3)
d 17.3,
4.4.2. (R)-2-(2-Methoxyethyl)cyclohexanone: (R)-318. Chiral GLC
17.5, 19.7, 22.1, 22.9, 23.1, 28.7, 31.3, 36.8, 45.9, 208.6; IR (ATR)
1708.6 (C]O) cmꢀ1; MS (EI) m/z: 168 (Mþ), 145, 126, 111, 98 (base
peak); HRMS (EI) m/z: (Mþ) calcd for C11H20O, 168.1514; found,
168.1517.
analysis, tR¼24.6 (R), 25.3 (S) min (SUPERCO,
a
[q
-DEX120, 100 ꢃC).
]¼þ1880, D3¼þ0.57
[
a]
25 þ1.1 (c 8.68, CHCl3) (68% ee). CDCHCl3
D
(94% ee). 1H NMR (400 MHz, CDCl3)
d 1.45e1.33 (m, 2H), 1.75e1.60
(m, 2H), 1.90e1.81 (m, 1H), 2.10e2.02 (m, 1H), 2.18e2.10 (m, 2H),
2.36e2.27 (m, 1H), 2.44e2.36 (m, 1H), 2.53e2.45 (m, 1H), 3.31 (s,
3H), 3.39 (ddd, J¼5.9, 6.9, 9.4 Hz, 1H), 3.43 (ddd, J¼5.9, 6.5, 9.4 Hz,
4.4.8. 2-Propylcyclohexanone: 9. Chiral GLC analysis, tR¼17.3,
17.6 min (SUPERCO, a
-DEX120, 90 ꢃC).
1H); 13C NMR (100 MHz, CDCl3)
d
25.0, 28.0, 29.3, 34.2, 42.1, 47.1,
1H NMR (400 MHz, CDCl3)
d
0.899 (t, J¼7.2 Hz, 3H), 1.13e1.24 (m,
58.4, 213.0; IR (ATR) 1706.7 (C]O) cmꢀ1; MS (EI) m/z: 156 (Mþ), 98
(base peak); HRMS (EI) m/z: (Mþ) calcd for C9H16O2, 156.1150;
found, 156.1152.
1H), 1.24e1.35 (m, 2H), 1.34e1.44 (m, 1H), 1.59e1.81 (m, 3H),
1.81e1.89 (m, 1H), 1.96e2.06 (m, 1H), 2.06e2.14 (m, 1H), 2.23e2.33
(m, 2H), 2.39 (dddd, J¼1.4, 4.3, 4.4, 13.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d 14.1, 20.2, 24.7, 27.9, 31.4, 33.7, 41.8, 50.4, 213.6; IR (ATR)
4.4.3. (R)-2-Allylcyclohexanone:
was purchased from Aldrich and used without further purification.
(R)-418. (ꢁ)-Allylcyclohexanone
1706.7 (C]O) cmꢀ1; MS (EI) m/z: 140 (Mþ), 111, 98 (base peak);
HRMS (EI) m/z: (Mþ) calcd for C9H16O, 140.1201; found, 140.1203.
Chiral GLC analysis, tR¼24.6 (R), 25.2 (S) min (SUPERCO,
a-
DEX120, 90 ꢃC).
Acknowledgements
25
[
a]
þ8.7 (c 1.08, MeOH) (68% ee). CDCHCl3
[q]¼þ1970,
D
D3¼þ0.60 (78% ee).
This work was supported in part by a Grant-in-Aid for Scientific
Research (C, 19590028) from the Ministry of Education, Culture,
Sports, Science and Technology of Japan. We are also thankful to
MEXT.SENRYAKU, 2008.
4.4.4. (R)-2-(4-Methylbenzyl)cyclohexanone: (R)-5. Chiral HPLC
analysis, tR¼28.0 (R), 37.3 (S) min (DAICEL CHIRALCEL AD, hexane/
isopropanol¼999/1, flow rate 0.5 mL/min, UV254).
24
[
a]
þ36.0 (c 1.00, CHCl3) (78% ee). CDCHCl3
[
q
]¼þ2058,
D
Supplementary data
D3¼þ0.624 (78% ee). 1H NMR (400 MHz, CDCl3)
d
1.34 (dddd, J¼3.5,
11.9, 11.9, 13.3 Hz, 1H), 1.51e1.63 (m, 1H), 1.61e1.74 (m, 1H), 1.82
(dddd, J¼1.6, 3.8, 7.5, 11.2 Hz, 1H), 1.98e2.09 (m, 2H), 2.27e2.36 (m,
1H), 2.31 (s, 3H), 2.37 (dd, J¼9.0, 14.1 Hz, 1H), 2.39e2.47 (m, 1H),
2.48e2.56 (m, 1H), 3.19 (dd, J¼4.7, 13.9 Hz, 1H), 7.04 (d, J¼8.0 Hz,
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.09.085.
References and notes
2H), 7.08 (d, J¼8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 20.9, 24.9,
27.9, 33.2, 34.9, 42.0, 52.4, 128.8, 128.9, 135.3, 137.1, 212.6; IR (ATR)
1706.7 (C]O) cmꢀ1; MS (EI) m/z: 202 (Mþ), 173, 159, 105 (base
peak), 97; HRMS (EI) m/z: (Mþ) calcd for C14H18O, 202.1358; found,
202.1362.
1. Duhamel, L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron: Asymmetry 2004, 15,
3653e3691.
2. Eames, J.; Weerasooriya, N. Tetrahedron: Asymmetry 2001, 12, 1e24.
3. Yanagisawa, A.; Yamamoto, H. In Comprehensive Asymmetric Catalysis; Jacobsen,
E. N., Pfalts, A., Yamamoto, H., Eds.; Springer: New York, NY, 1999; Vol. 3,
pp 1295e1306; Yanagisawa, A.; Yamamoto, H. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfalts, A., Yamamoto, H., Eds.; Springer: New York, NY,
2004; pp 125e132; Supplement 2.
4.4.5. (R)-2-Benzylcycloheptanone: (R)-619. Chiral HPLC analysis,
tR¼12.0 (R), 16.7 (S) min (DAICEL CHIRALCEL OJ, hexane/iso-
4. Hughes, D. L. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfalts, A.,
Yamamoto, H., Eds.; Springer: New York, NY, 1999; Vol. 3, pp 1273e1294;
Hughes, D. L. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfalts, A.,
Yamamoto, H., Eds.; Springer: New York, NY, 2004; pp 161e169; Supplement 1.
5. Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37, 580e591.
propanol¼9/1, flow rate 0.5 mL/min, UV254).
21
[
a]
þ19.2 (c 1.00, CHCl3) (27% ee). 1H NMR (400 MHz, CDCl3)
D
d
1.26e1.40 (m, 3H), 1.56e1.68 (m, 1H), 1.72e1.90 (m, 4H),
2.42e2.48 (m, 2H), 2.56 (dd, J¼8.4, 13.7 Hz, 1H), 2.77e2.86 (m, 1H),
ꢀ
6. d’Angelo, J.; Desmaele, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry
3.08 (dd, J¼5.9, 13.7 Hz, 1H), 7.13e7.21 (m, 3H), 7.24e7.30 (m, 2H);
1992, 3, 459e505.
13C NMR (100 MHz, CDCl3)
d 24.1, 28.5, 29.2, 30.2, 37.8, 43.1, 53.5,
7. Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
2253e2329.
125.9, 128.2, 129.0, 139.9, 215.5; IR (ATR) 1697.0 (C]O) cmꢀ1; MS
(EI) m/z: 202 (Mþ, base peak), 159, 145, 91; HRMS (EI) m/z: (Mþ)
calcd for C14H18O, 202.1358; found, 202.1357.
8. Toda, F.; Shinyama, T. J. Chem. Soc., Perkin Trans. 1 1997, 1759e1761.
9. Matsumoto, K.; Okamoto, T.; Otsuka, K. Bull. Chem. Soc. Jpn. 2004, 77,
2051e2056.
10. Sakai, K.; Sakurai, R.; Yuzawa, A.; Hirayama, N. Tetrahedron: Asymmetry 2003,
14, 3713e3718.
11. Tsunoda, T.; Kaku, H.; Nagaku, M.; Okuyama, E. Tetrahedron Lett. 1997, 38,
7759e7760.
12. Kaku, H.; Ozako, S.; Kawamura, S.; Takatsu, S.; Ishii, M.; Tsunoda, T. Heterocycles
2001, 55, 847e850.
13. Seebach, D.; Beck, A. K.; Imwikelried, R.; Roggo, S.; Wonnacott, A. Helv. Chim.
Acta 1987, 70, 954e974.
14. Kaku, H.; Takaoka, S.; Tsunoda, T. Tetrahedron 2002, 58, 3401e3407.
15. Kaku, H.; Okamoto, N.; Nakamaru, A.; Tsunoda, T. Chem. Lett. 2004, 33, 516e517.
16. Kaku, H.; Okamoto, N.; Nishii, T.; Horikawa, M.; Tsunoda, T. Synthesis 2010,
2931e2934.
4.4.6. (R)-2-Prenylcyclohexanone: (R)-7. Chiral GLC analysis,
tR¼18.8 (R), 19.2 (S) min (SUPERCO,
a
-DEX120, 120 ꢃC).
22
[
a]
þ22.7 (c 1.01, CHCl3) (99% ee). CDCHCl3
[q
]¼þ2100,
D
D3¼þ0.636 (99% ee). 1H NMR (400 MHz, CDCl3)
d
1.35 (dddd, J¼3.9,
11.9, 11.9, 13.1 Hz, 1H), 1.58e1.74 (m, 2H), 1.60 (d, J¼0.4 Hz, 3H), 1.69
(d, J¼1.0 Hz, 3H), 1.81e1.89 (m, 1H), 1.96 (ddd, J¼7.4, 8.0, 14.7 Hz,
1H), 2.00e2.08 (m, 1H), 2.08e2.16 (m, 1H), 2.24e2.34 (m, 2H),
2.36e2.46 (m, 2H), 5.08 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 17.7,
17. See Ref. 12.
24.9, 25.7, 27.7, 27.9, 32.3, 41.9, 51.0, 121.9, 132.9, 213.1; IR (ATR)
1708.6 (C]O) cmꢀ1; MS (EI) m/z: 166 (Mþ), 111, 98 (base peak);
HRMS (EI) m/z: (Mþ) calcd for C11H18O, 166.1358; found, 166.1355.
18. Meyers, A. I.; Williams, D. R.; Erickson, G. W.; White, S.; Druelinger, M. J. Am.
Chem. Soc. 1981, 103, 3081e3087.
19. Lu, S.-M.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 8920e8923.