A method to prepare optically active acyclic α-benzyl ketones by thermodynamically controlled deracemization

Article abstract of DOI:10.1002/ejoc.201300936

Thermodynamically controlled deracemization of some acyclic ketones bearing a chiral center at the position α to the carbonyl group was satisfactorily achieved. Acyclic ketones with high optical purities could be isolated after treatment of the racemic ketones with base in aqueous MeOH in the presence of (-)-(2R,3R)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro[5. 4]decane (1a). The efficiency of the deracemization was appreciably influenced by the ratio of H₂O/MeOH used as solvent. Racemic ketones bearing a chiral center at the position α to the carbonyl group were converted into optically active ketones in the presence of TADDOL-type host molecule 1a in H₂O/MeOH in suspension in basic media. Copyright

Full text of DOI:10.1002/ejoc.201300936

FULL PAPER
DOI: 10.1002/ejoc.201300936
A Method to Prepare Optically Active Acyclic α-Benzyl Ketones by
Thermodynamically Controlled Deracemization
Hiroto Kaku,*[a] Takahiro Imai,[a] Risa Kondo,[a] Shiho Mamba,[a] Yu Watanabe,[a]
Makoto Inai,[a][‡] Takeshi Nishii,[a] Mitsuyo Horikawa,[a] and Tetsuto Tsunoda*[a]
Keywords: Deracemization / Chiral resolution / Host–guest systems / Inclusion compounds / Molecular recognition /
Ketones
Thermodynamically controlled deracemization of some
acyclic ketones bearing a chiral center at the position α to
the carbonyl group was satisfactorily achieved. Acyclic
ketones with high optical purities could be isolated after
treatment of the racemic ketones with base in aqueous
MeOH in the presence of (–)-(2R,3R)-trans-2,3-bis(hydroxy-
diphenylmethyl)-1,4-dioxaspiro[5.4]decane (1a). The effi-
ciency of the deracemization was appreciably influenced by
the ratio of H2O/MeOH used as solvent.
influenced by the ratio of solvents. We went on to improve
the method for the preparation of optically active α-mono-
Introduction
We have previously reported a thermodynamically con- substituted cycloalkanones with higher optical purities.[4]
trolled deracemization process[1–6] for the preparation of For instance, after mixing (Ϯ)-2a and 1a with NaOH in a
optically active α-monosubstituted cycloalkanones using 3:7 mixture of H2O/MeOH as the solvent, followed by fil-
chiral host molecules in suspension in basic media. For ex- tration to recover the inclusion complex of 1a and (R)-2a
ample, the use of (–)-(2R,3R)-trans-2,3-bis(hydroxydiphen- (deracemization step), the complex was suspended again in
ylmethyl)-1,4-dioxaspiro[5.4]decane (1a) or (–)-(4R,5R)- a fresh mixture of H2O/MeOH (3:7) without NaOH (re-
trans-4,5-bis(hydroxydiphenylmethyl)-2-phenyl-1,3-dioxol- complexation step) to give (R)-2a in 71% yield and with
ane (1b; 1.0 equiv.) as host molecules with a base in aque- 93% ee (Method B, Scheme 2). For ketone (Ϯ)-2b in a 7:3
ous MeOH converted racemic 2-benzylcyclohexanone (2a) mixture of H2O/MeOH, the optical purity of (R)-2b was
and 2-allylcyclohexanone (2b) into their (R) isomers in 74 also increased to 93% ee when 1b was used.
and 62% ee, respectively, in quantitative yields (Method A,
We considered that deracemization could provide an ex-
cellent convenient method for preparing optically active α-
Scheme 1).[1–3]
Furthermore, we found that the efficiency of the thermo- monosubstituted cycloalkanones. We therefore demon-
dynamically controlled deracemization process was strongly strated the utility of this method by carrying out the asym-
Scheme 1. Deracemization of (Ϯ)-2-benzyl- and (Ϯ)-2-allylcyclohexanone (Method A).
[a] Faculty of Pharmaceutical Sciences, Tokushima Bunri
metric synthesis of natural products starting from the chiral
University
cycloalkanones obtained.[4,5] Additional X-ray crystallo-
Tokushima 770-8514, Japan
E-mail: kaku@ph.bunri-u.ac.jp
graphic studies revealed the nature of the host–guest molec-
ular recognition process in the inclusion complex.[6] As part
of our continued studies into the scope and limitations of
deracemization, we focused on the reaction with acyclic
ketones 3–14 bearing a benzyl moiety at the α-position of
the carbonyl group. Since acyclic ketones are conformation-
tsunoda@ph.bunri-u.ac.jp
http://p.bunri-u.ac.jp/english
[‡] Present address: School of Pharmaceutical Science, University
of Shizuoka
52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300936.
8208
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8208–8213

Thermodynamically Controlled Deracemization
Scheme 2. Improved deracemization of (Ϯ)-2-benzyl- and (Ϯ)-2-allylcyclohexanone (Method B).
ally more flexible than cyclic ones, the achievement of dera- Table 1. Deracemization of (Ϯ)-acyclic ketones (Method A).[a]
cemization of such acyclic ketones is quite interesting.
Furthermore, the development of a method to prepare op-
tically active acyclic ketones remains a challenge in organic
synthesis.[7,8] In this paper, we describe our results in detail.
Results and Discussion
To explore the possibility of deracemization of acyclic
ketones, we carried out Method A (see Experimental Sec-
tion) using host 1a. Ketones were treated with NaOH in
50% aqueous MeOH, and after neutralization and extrac-
tion, the resulting mixture was purified by SiO2 column
chromatography to recover the ketones, whose optical pu-
rity was determined by HPLC using chiral columns. The
absolute configuration of the guest molecules (i.e., the
ketones) was determined as follows. For recovered ketones
3, 4, and 5, their specific optical rotations were compared
to literature data.[9] Compound 7 was converted into 5 by
hydrogenation, and this compound 5 was analyzed by
HPLC using a chiral column and compared to an authentic
sample of 5 obtained in this study. Ketones 6 and 11 were
subjected to Baeyer–Villiger oxidation using mCPBA (m-
chloroperbenzoic acid). The resulting esters were hydro-
lyzed to give secondary alcohols, whose absolute configura-
tions were determined by a modified Mosher’s method.[10]
Ketone 9 was converted to 1-phenylbutan-2-ol, also by
Baeyer–Villiger oxidation, followed by hydrolysis. The re-
Entry
Guest
Recovery of guest
Yield [%][b]
ee [%]
Config.
1
2
3
4
5
6
7
8
9
3
4
83
95
94
92
91
90
94
97
98
94
93
99
0
66
72
64
44
0
44
0
82
0
–
(S)
(S)
(R)
(S)
–
(R)
–
(R)
–
5
6
7
8
9
10
11
12
13
14
10
11
12
0
90
–
(S)
[a] (Ϯ)-Ketone (100 mg), 1a (1.0 equiv.), NaOH (4.0 equiv.), H2O/
MeOH (1:1; 10 mL) at room temp., 2 d. [b] Isolated yield.
sulting alcohol was analyzed by HPLC using a chiral col- covered from the solid material by SiO2 column chromatog-
umn, and the eluted peak product was compared to the raphy were plotted against the percentage of water in the
authentic alcohol derived from 11 obtained in this study. aqueous MeOH mixture used as solvent. The results for
The absolute configuration of 14 was determined by X-ray acyclic ketones 3–14 using 1a are shown in Figure 1.
crystallographic analysis of an inclusion complex of (S)-14
In all cases, when the proportion of water in the solvent
and 1a.[11] The results are listed in Table 1. Although only was low, the ketones were not recovered from the solid ma-
racemic ketones were recovered in the cases of 3, 8, 10, 12, terial, because of their high solubility in the solvent. How-
and 13, the other ketones (i.e., 4, 5, 6, 7, 9, 11, and 14) were ever, when the proportion of water was increased, the recov-
converted into optically active compounds with moderate ery of ketones increased remarkably, because of the forma-
to good optical purities in quantitative yields. We were not tion of a true inclusion complex with the host molecules
able to predict which enantiomer [(R) or (S)] of the guest and/or because of adhesion onto the surface of the host
molecule would be included by the host molecule 1a, be- molecules. In the case of 5, the (S) isomer was recovered in
cause the precise details of this chiral molecular recognition excellent optical purity, irrespective of the percentage of
process are not yet clear.
water in the solvent mixture. The yield of recovered 5 in-
As these preliminary studies showed that we could creased to 95% with 96% ee when 80% water was used.
achieve the deracemization of acyclic ketones to some ex- Thus, the resolution efficiency (E)[12] of the deracemization
tent, we continued with our investigation of this conversion. of 5 was quite high, reaching levels up to E = 186%. In
To precisely evaluate the efficiency of the molecular re- contrast, in the cases of 4, 6, 7, 9, 11, and 14, the optical
cognition process, the solid material was separated from the purities of the recovered ketones tended to decrease as the
liquid phase by filtration after deracemization (scheme in yield increased, probably because of adhesion of the ketone
Figure 1). The yields and optical purities of the ketones re- to the solid phase.[4] Nevertheless, single enantiomers of 4,
Eur. J. Org. Chem. 2013, 8208–8213
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8209

H. Kaku, T. Tsunoda et al.
FULL PAPER
Figure 1. The experiments were carried out using a binary solvent system composed of H2O and MeOH. On the x-axis, the proportion
of water (%) in the solvent is given. The yield (%) (red dots) and optical purity [ee (%); blue squares] of recovered guest molecules 3–14
from the solid are plotted. The vertical green line represents the ratio of H2O/MeOH that provided the optimum optical purity and best
recovery of the desired product.
8210
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8208–8213

Thermodynamically Controlled Deracemization
Table 2. Deracemization of (Ϯ)-acyclic ketones using Method B.[a]
Entry
Guest
H2O/MeOH
Recovery of guest
Yield [%][b]
ee [%]
Config.
E [%][c]
1
2
3
4
5
6
7
8
3
4
4:1
3:2
4:1
1:1
3:2
1:1
1:1
1:1
56
72
93
52
38
33
82
88
48
Ͼ99
Ͼ99
94
93
98
S
S
S
R
S
R
R
S
54
144
186
98
71
65
5
6
7
9
11
14
99
Ͼ99
162
176
[a] (Ϯ)-Ketone (100 mg), 1a (1.0 equiv.), NaOH (4.0 equiv.), H2O/MeOH (10 mL) at room temp., 2 d. [b] Isolated yield. [c] See ref.[12]
6, 7, 9, 11, and 14 were efficiently included by host molecule we subjected the residue to chromatography on silica gel to
1a in less than 50–60% water. In the case of 3, the chiral recover the (R) isomer in 78% yield with 48% ee (green line
molecular recognition by 1a was only moderate in any pro- in Figure 1a).
portion of water. On the other hand, isopropyl ketones 12
and 13 were presumably not included by 1a because of their
Conclusions
bulk. So in these cases, the ketones simply adhered to the
surface of the solid phase (i.e., host 1a) and were recovered
as a racemate. Furthermore, we assume that 1a could not
distinguish between the enantiomers of ketones 8 and 10[13]
in the respective inclusion complexes, because the molecular
sizes of 8 and 10 are smaller than those of 9 and 11, which
were efficiently included by host molecule 1a. That is to say,
both enantiomers of 8 and 10 were included in the cavity
formed by the aggregate of host molecule 1a, so the racemic
ketones were recovered from the solid phase. Thus, al-
though the efficiency of the deracemization was influenced
by the solubility of the guest molecules in aqueous MeOH,
and also by their structural features such as the length of
the alkyl chain and their steric bulk, optically active acyclic
ketones were obtained satisfactorily by deracemization in
several cases.
Based on the findings outlined in Figure 1, we carried
out Method B (see Experimental Section) as an improved
procedure for deracemization. In particular, we were able to
define effective ratios of H2O/MeOH (green lines in Fig-
ure 1) for the solvent. The results for 3–7, 9, 11, and 14 are
shown in Table 2. Since the chiral molecular recognition of
8, 10, 12, and 13 with host 1a was not promising (Figure 1),
these compounds were not considered in this study.
We have found that the efficiency of thermodynamically
controlled deracemization was appreciably influenced by
the ratio of the H2O/MeOH binary mixture used as a sol-
vent, and we accomplished satisfactory thermodynamically
controlled deracemization of some acyclic ketones bearing
a chiral center at the position α to the carbonyl group. This
process resulted in acyclic ketones with high optical purit-
ies. Further studies to discover the mechanism of the molec-
ular recognition process and the applicability of the method
are in progress.
Experimental Section
General Remarks: Infrared (IR) spectra were recorded using the
ATR (attenuated total reflectance) technique with a JASCO Model
FTIR-410 spectrophotometer. Proton nuclear magnetic resonance
spectra (1H NMR) were recorded with Varian 400 MR (400 MHz)
or Mercury 300 (300 MHz) spectrometers in CDCl3. Chemical
shifts are reported in parts per million on the δ scale relative to
internal Me4Si (δ = 0.00 ppm), and coupling constants are given in
Hertz. 13C NMR spectra were obtained with a Varian 400 MR
(100 MHz) instrument, and chemical shifts are referenced to the
residual solvent signal (CDCl3: δ = 77.0 ppm). Mass spectra, in-
cluding high-resolution mass spectra, were recorded with a JEOL
AX-500 spectrometer. Optical rotations were measured with a JA-
SCO DIP-1000 polarimeter using a 1 cm microcell. Analytical
HPLC was performed with a JASCO system consisting of a pump
(PU-980) and a photodiode array detector (UV-970, set at 254 nm),
and equipped with a Daicel column: CHIRALCEL OJ or OD or
CHIRALPAK AD connected to IA. Peak areas were measured by
electronic integration using a LASOFT.co.jp CDS-Lite Chromato-
pac. In general, reagent-grade solvents were used. Anhydrous
dichloromethane and THF were purchased from KANTO Chemi-
For all cases except for 3, optically highly pure ketones
could be recovered as expected, although in some cases, the
yields of the recovered ketones were low, because some of
the ketones dissolved and were removed in the solvent dur-
ing the filtration step. Since the guest (S)-14 was recognized
effectively by host 1a (see green line in Figure 1l), no ad-
ditional suspension was needed, and the solid complex was
recovered by filtration. In contrast, Method B showed poor
efficiency in the case of 3, giving only a 56% yield of the
(R) isomer with 48% ee. Therefore, after the first filtration, cal Co. Inc. N,N-Dimethylformamide (DMF) was distilled from
Eur. J. Org. Chem. 2013, 8208–8213
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8211

H. Kaku, T. Tsunoda et al.
FULL PAPER
CaH2 under reduced pressure. Triethylamine was distilled from
CaH2 under argon. Analytical thin layer chromatography (TLC)
was performed on precoated silica gel 60 F-254 plates (0.2 mm
layers) on glass with a fluorescent indicator, supplied by E. Merck.
For column chromatography, Fuji Silysia BW-127ZH (100–
270 mesh) or BW-300 (200–400 mesh) silica was used. Known race-
mic ketones 3–7 were prepared by acetoacetic ester synthesis fol-
lowed by decarboxylation. Ketones 8, 11, and 14 were synthesized
by α-benzylation of the corresponding ketones. Ketones 9 and 10
were prepared by Weinreb ketone synthesis[14] from the correspond-
ing α-benzylcarboxylic acids. Isopropyl ketones 12 and 13 were pre-
pared by α-benzylation of ethyl isobutyrylacetate followed by
Krapcho dealkoxycarbonylation[15] (see Supporting Information).
of the ketone was determined by HPLC using chiral columns
(Daicel, CHIRALCEL OJ or OD, or CHIRALPAK AD connected
to IA). The yields and optical purities of the guest compound were
plotted against the proportion of water in the H2O/MeOH binary
solvent mixture (Figure 1).
General Procedure for Method B: Table 2. Compound 1a
(1.0 equiv.), NaOH (1 m aq.; 4.0 equiv.), and distilled water were
successively added to a solution of a ketone (100 mg) in MeOH in
a 10 mL flask with a glass stopper. By considering Figure 1, the
optimum ratio of water/methanol was determined (green lines). The
total volume of solvent was adjusted to 10 mL.[16] The resulting
suspension was stirred vigorously at ambient temperature for 2 d.
The mixture was filtered, and the residue was washed with the se-
lected mixture of H2O/MeOH (3ϫ 2 mL). The resulting white solid
was dissolved in diethyl ether, dried with MgSO4, filtered, and con-
centrated. The residue was suspended again in a fresh mixture of
H2O/MeOH (the selected mixture of H2O/MeOH, 10 mL) at ambi-
ent temperature for 1 d. After filtration followed by washing with
H2O/MeOH (the selected mixture of H2O/MeOH, 3ϫ 2 mL), the
residue was dissolved in diethyl ether. The resulting solution was
dried with MgSO4 and filtered, and the solvent was evaporated.
The residue was purified by silica gel column chromatography (n-
hexane/diethyl ether grad.) to give the ketone as a colorless oil, and
also recovered 1a. The optical purity of the ketone was determined
by HPLC using chiral columns (Daicel, CHIRALCEL OJ or OD,
or CHIRALPAK AD connected to IA).
General Procedure for Method A: Procedure for Table 1. Com-
pound 1a (1.0 equiv.), distilled water, and NaOH (1 m aq.;
4.0 equiv.) were successively added to a solution of a ketone
(100 mg) in MeOH (5 mL) in a 10 mL flask with a glass stopper.
The total volume of solvent was adjusted to 10 mL.[16] The re-
sulting suspension was stirred vigorously at ambient temperature
for 2 d. The mixture was poured into ammonium chloride (satu-
rated aq.; ca. 20 mL) and extracted with diethyl ether (3ϫ ca.
30 mL). The combined organic extracts were dried with MgSO4,
filtered, and concentrated. The residue was purified by silica gel
column chromatography (n-hexane/diethyl ether, grad.) to give the
ketone product as a colorless oil, and also recovered 1a. The optical
purity of the ketone was determined by HPLC using chiral columns
(Daicel, CHIRALCEL OJ or OD, or CHIRALPAK AD connected
to IA).
Typical Procedure for Method B: Table 2, Entry 3. Compound 1a
(267 mg, 0.527 mmol), distilled H2O (5.9 mL) and, NaOH (1 m aq.;
2.1 mL, 3.96 mmol) were successively added to a solution of 5
(101 mg, 0.531 mmol) in MeOH (2.0 mL) in a 10 mL flask with a
glass stopper.[16] The ratio of H2O/MeOH was 4:1 (see green line
in Figure 1c). The resulting suspension was stirred vigorously at
ambient temperature for 2 d. The mixture was filtered, and the resi-
due was washed with a mixture of H2O/MeOH (4:1; 3ϫ 2 mL).
The resulting white solid was dissolved in diethyl ether, and the
resulting solution was dried with MgSO4, filtered, and concen-
trated. The residue was suspended again in a fresh mixture of H2O/
MeOH (4:1; 10 mL) and left at ambient temperature for 1 d. After
Typical Procedure for Method A: Table 1, Entry 3. Compound 1a
(269 mg, 0.530 mmol, 1.0 equiv.), distilled water (2.88 mL), and
NaOH (1 m aq.; 2.12 mL) were successively added to a solution of
3-benzylhexan-2-one (5; 100 mg, 0.532 mmol) in MeOH (5 mL) in
a 10 mL flask with a glass stopper.[16] The resulting suspension was
stirred vigorously at ambient temperature for 2 d. The mixture was
poured into ammonium chloride (saturated aq.; ca. 50 mL) and
extracted with diethyl ether (3ϫ ca. 50 mL). The combined organic
extracts were dried with MgSO4, filtered, and concentrated. The
residue was purified by silica gel column chromatography (n-hex-
ane/diethyl ether, grad.) to give (S)-5 (95.4 mg, 94%; 72% ee) as a filtration followed by washing with H2O/MeOH (4:1; 3ϫ 2 mL),
colorless oil, and also recovered 1a. Chiral HPLC analysis (Daicel
CHIRALCEL OJ; n-hexane/2-propanol, 99:1; flow rate 0.5 mL/
min; UV254): tR = 13.3 (S), 18.4 (R) min. 1H NMR (400 MHz,
CDCl3): δ = 7.27 (m, 2 H), 7.19 (m, 1 H), 7.16–7.12 (m, 2 H), 2.88
(dd, J = 8.2, 12.4 Hz, 1 H), 2.83 (m, 1 H), 2.68 (dd, J = 5.3,
the residue was dissolved in diethyl ether. The resulting solution
was dried with MgSO4 and filtered, and the solvent was evapo-
rated. The residue was purified by silica gel column chromatog-
raphy (n-hexane/diethyl ether, grad.) to give (S)-5 (94.0 mg, 93%;
Ͼ99% ee) as a colorless oil. The optical purity of the ketone was
12.4 Hz, 1 H), 1.99 (s, 3 H), 1.67–1.56 (m, 1 H), 1.48–1.38 (m, 1 determined by HPLC using chiral columns (Daicel, CHIRALCEL
H), 1.37–1.20 (m, 2 H), 0.89 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR OJ). [α]1D9 = +29.5 (c = 1.00, CHCl3; 82% ee) {ref.[8g] [α]2D6 = +28.9
(100 MHz, CDCl3): δ = 212.55, 139.67, 128.81, 128.44, 126.22,
[c = 0.9, CHCl3; (S) isomer]}
54.55, 37.92, 33.84, 30.19, 20.49, 14.13 ppm. IR (ATR): ν = 1712.5
˜
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic procedures for racemic ketones 9, 12, and 13, and
also characterization of racemic ketones 3–14; 1H and 13C NMR
spectra of the compounds described; HPLC traces of racemic and
optically active ketones 3–7, 9, 11, and 14; X-ray crystal structure
and preparation procedure for a complex of 1a and (S)-14.
(C=O) cm–1. MS (EI): m/z (%) = 190 [M]+, 175, 147, 91 (100).
HRMS: calcd. for C13H18O [M]+ 190.1358; found 190.1365.
Solvent Dependence of Deracemization: Procedure for Figure 1.
Compound 1a (1.0 equiv.), NaOH (1 m aq.; 4.0 equiv.), and dis-
tilled water were successively added to a solution of a ketone
(100 mg) in MeOH in a 10 mL flask with a glass stopper. The total
volume of solvent was adjusted to 10 mL.[16] The resulting suspen-
sion was stirred vigorously at ambient temperature for 2 d. The
mixture was filtered, and the residue was washed with the selected
mixture of H2O/MeOH (3ϫ 2 mL). The resulting white solid was
dissolved in diethyl ether, and the solution was dried with MgSO4,
filtered, and concentrated. The residue was purified by silica gel
column chromatography (n-hexane/diethyl ether, grad.) to give the
ketone as a colorless oil, and also recovered 1a. The optical purity
Acknowledgments
This work was supported by the Japan Society for the Promotion
of Scinece (KAKENHI JSPS) by a Grant-in-Aid for Scientific Re-
search (grant numbers 23590034 and 22590032). We are also grate-
ful to the MEXT-Supported Program for the Strategic Research
Foundation at Private Universities, 2008–2012.
8212
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8208–8213

Thermodynamically Controlled Deracemization
13248–13251; f) Matteson asymmetric homologation: M. V.
Rangaishenvi, B. Singaram, H. C. Brown, J. Org. Chem. 1991,
56, 3286–3294; g) asymmetric hydrogenation of α,β-unsatu-
rated ketones: S.-M. Lu, C. Bolm, Angew. Chem. 2008, 120,
9052; Angew. Chem. Int. Ed. 2008, 47, 8920–8923, and refer-
ences cited therein.
[1]
[2]
[3]
[4]
T. Tsunoda, H. Kaku, M. Nagaku, E. Okuyama, Tetrahedron
Lett. 1997, 38, 7759–7760.
H. Kaku, S. Ozako, S. Kawamura, S. Takatsu, M. Ishii, T. Tsu-
noda, Heterocycles 2001, 55, 847–850.
H. Kaku, N. Okamoto, A. Nakamaru, T. Tsunoda, Chem. Lett.
2004, 33, 516–517.
[9] a) For 3, see ref.[8f]; b) for 4, see: M. Larcheveque, E. Ignatova,
T. Cuvigny, J. Organomet. Chem. 1979, 177, 5–15; c) for 5, see
ref.[8g]
H. Kaku, A. Nakamaru, M. Inai, T. Nishii, M. Horikawa, T.
Tsunoda, Tetrahedron 2010, 66, 9450–9455.
[10] I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem.
Soc. 1991, 113, 4092–4096.
[5] H. Kaku, N. Okamoto, T. Nishii, M. Horikawa, T. Tsunoda,
Synthesis 2010, 17, 2931–2934.
[11] CCDC-936063 [for complex of (S)-14 and 1a] contains the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[12] Resolution efficiency E = yield [%] ϫ enantiomeric excess [%]
ϫ 2/100. For optical resolutions, the value of E never exceeds
100%. See: K. Sakai, R. Sakurai, A. Yuzawa, N. Hirayama,
Tetrahedron: Asymmetry 2003, 14, 3713–3718.
[13] The smallest methyl ketone 3 was included with a moderate ee
by 1a. Although X-ray analysis of the inclusion complex could
not be achieved, we assumed that the conformation of 3 in the
inclusion complex was different from that of 8 and 10.
[14] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815–
3818.
[15] A. P. Krapcho, E. G. E. Jahngen, A. J. Lovey, F. W. Short, Tet-
rahedron Lett. 1974, 15, 1091–1094.
[16] When a larger flask was used, the efficiency of the deracemiza-
tion decreased dramatically, because of adhesion of the host
molecule onto the inside wall surface of the flask.
Received: June 25, 2013
[6] H. Kaku, S. Takaoka, T. Tsunoda, Tetrahedron 2002, 58, 3401–
3407.
[7] Only one paper reporting the deracemization of acyclic ketones
was found in the literature. Matsumoto and co-workers carried
out the reaction of acyclic α-hydroxy ketones. See: K. Matsum-
oto, K. Otsuka, T. Okamoto, H. Mogi, Synlett 2007, 729–732.
[8] Several methods to prepare optically active acyclic carbonyl
compounds with a chiral center at the α-position have been
reported in the literature. See, for example: a) asymmetric α-
alkylation of ketones, esters, and their synthetic equivalents:
S. E. Wengryniuk, D. Lim, D. M. Coltart, J. Am. Chem. Soc.
2011, 133, 8714–8720; b) asymmetric aldol reactions: R.
Mahrwald (Ed.), Modern Aldol Reactions, Wiley-VCH,
Weinheim, 2004; c) asymmetric [3,3]-sigmatropic rearrange-
ments: K. Mikami, K. Akiyama in The Claisen Rearrangement:
Methods and Applications (Eds.: M. Hiersemann, U. Nubbeme-
yer), Wiley-VCH, Weinheim, 2007, chapter 2, pp. 25–43; d) C.
Uyeda, E. N. Jacobsen, J. Am. Chem. Soc. 2011, 133, 5062–
5075; e) enantioselective protonation of enol ethers: C. H.
Cheon, O. Kanno, F. D. Toste, J. Am. Chem. Soc. 2011, 133,
Published Online: October 22, 2013
Eur. J. Org. Chem. 2013, 8208–8213
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8213