Asymmetric electrochemical oxidation of 1,2-diols, aminoalcohols, and?aminoaldehydes in the presence of chiral copper catalyst

Article abstract of DOI:10.1016/j.tet.2008.05.015

Asymmetric oxidation of 1,2-diols, aminoalcohols, and aminoaldehydes in the presence of copper(II) triflate and (R,R)-Ph-BOX was accomplished by electrochemical method using Br^- as a mediator. This oxidation was applicable to kinetic resolution of racemic cis-cycloalkane-1,2-diols, aminoalcohols, and aminoaldehydes to afford optically active compounds with good to high enantioselectivity.

Full text of DOI:10.1016/j.tet.2008.05.015

Tetrahedron 64 (2008) 6675–6683
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric electrochemical oxidation of 1,2-diols, aminoalcohols,
and aminoaldehydes in the presence of chiral copper catalyst
*
Daishirou Minato, Hitomi Arimoto, Yoko Nagasue, Yosuke Demizu, Osamu Onomura
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 April 2008
Received in revised form 2 May 2008
Accepted 2 May 2008
Available online 9 May 2008
Asymmetric oxidation of 1,2-diols, aminoalcohols, and aminoaldehydes in the presence of copper(II)
triflate and (R,R)-Ph-BOX was accomplished by electrochemical method using Brꢀ as a mediator. This
oxidation was applicable to kinetic resolution of racemic cis-cycloalkane-1,2-diols, aminoalcohols, and
aminoaldehydes to afford optically active compounds with good to high enantioselectivity.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric electrochemical oxidation
Copper complex
1,2-Diol
a
-Ketoalcohol
Aminoalcohol
Aminoaldehyde
1. Introduction
known except for the two examples using semi-catalytic amount of
chiral dioxiranes5 or chiral hypervalent iodine.6
Selective oxidation of hydroxyl group to carbonyl group is a ba-
sic and important organic reaction. It was reported in 1974 that 1,2-
diols are selectively oxidized to the corresponding
In continuing the study, we succeeded in kinetic resolution of A0
by electrochemical oxidation. The concept we used in the asym-
a
-ketoalcohols
metric electrochemical oxidation of A0 to optically active
a-
by utilizing a stoichiometric amount of dibutyltinoxide (Bu2SnO),
which forms dibutylstannylenes followed by brominolysis.1 From
the standpoint of green chemistry, we have reported efficient oxi-
dation of 1,2-diols A by electrochemical method using a catalytic
ketoalcohols B0 is schematically represented in Scheme 1. Complex
D0 consisting diols A0 and chiral copper catalyst Cu–L
was easily
*
deprotonated by cathodically generated MeOꢀ to afford alkoxide
anions E0, which reacted with anodically generated Brþ to form
O-brominated intermediates F0. MeOꢀ removed HBr from F0 to
amount of Bu2SnO and Brꢀ ion to afford
a-ketoalcohols B in high
yield without 1,2-diketones C (Eq. 1).2
afford B0 and regenerate Cu–L
. Although the mechanism for this
*
oxidation is similar to that of the oxidation with NBS,3 this elec-
trochemical method is effective for some diols that NBS could not
oxidize. In addition, this method is applicable to the asymmetric
oxidation of aminoalcohols G0 and aminoaldehydes H0 to the
corresponding optically active aminoesters.
R
OH
R
R
O
O
-[e]
R
R
OH
OH
Bu2SnO (0.05 equiv)
+
ð1Þ
R
O
Et4NBr (0.2 equiv)
MeOH
A
B
C
up to 96% yield
~0%
More recently, we reported the first catalytic asymmetric oxi-
dation of 1,2-diols A0 to afford the corresponding optically active
-ketoalcohols B0 in high enantioselectivity,3 which is based on
recognition of the diol-moiety by copper(II) ion associated with
(R,R)-Ph-BOX complex4 to form the activated intermediates D0
followed by oxidation with NBS (Eq. 2). So far, to the best of our
knowledge, catalytic asymmetric oxidation of A0 to B0 has not been
2. Results and discussion
a
2.1. Accelerating effect based on recognition of the diol-
moiety under the electrochemical oxidation condition
First, we tried electrochemical oxidation of phenylcyclohexane-
cis-1,2-diol (cis-1) as a model compound to check for the acceler-
ating effect based on recognition of cis-1 with the Cu(II)–(R,R)-Ph-
BOX complex. The electrochemical oxidation of cis-1 in the
presence of Cu(OTf)2 and (R,R)-Ph-BOX predominantly afforded
* Corresponding author. Tel.: þ81 95 819 2429; fax: þ81 95 819 2476.
E-mail address: onomura@nagasaki-u.ac.jp (O. Onomura).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.015

6676
D. Minato et al. / Tetrahedron 64 (2008) 6675–6683
R2
H
O
R2
R2
R1
R1
R1
R1
O
O
R1
R1
OH
OH
Cu2+
L*
OH
NBS
Cu2+ L*
N
N
*
ð2Þ
K2CO3
O
H
Ph
O
Ph
2+
-
Cu
L*
L* (R,R)-Ph-BOX
A'
D'
B'
Br+
2e
Br-
2MeOH 2MeO- + H2
R1
R1
R2
OH
HO
A'
anode
2e
cathode
R1
O
R1
R2
Cu2+
O
R1
O
R1
R2
H
H
Cu2+
L*
*
D'
OH
L*
B'
L*: (R,R)-Ph-BOX
MeO-
MeOH
MeOH + Br-
MeO-
R1
R1
O
R1
R2
O
R1
R2
H
R4
R4
-
Br
O
O
H
R3
R3
OH
Cu2+
Cu2+
L*
N
N
CHO
Br+
L*
Bz
Bz
E'
F'
G'
H'
Scheme 1.
mono-oxidized product 2 (36% yield). However, the oxidation did
not proceed in the absence of Cu(OTf)2 and (R,R)-Ph-BOX (Eq. 3).
These results suggest that cis-1 might be recognized by the Cu(II)–
(R,R)-Ph-BOX complex under this oxidation condition.
solvent (5 mL). After passing through 2.0 F/mol of electricity at
constant current (50 mA) at 0 ꢂC and usual workup, optically active
a-ketoalcohol (S)-2 was obtained in 36% yield with moderate se-
lectivity (s) value of 8 (Table 1, entry 1).6–9 Comparable result was
obtained by use of CuBr2 instead of Cu(OTf)2 (entries 1 and 2).
Among the solvents tested, methanol was most suitable for this
reaction (entries 1, 3, and 4). Although the counter cation of elec-
trolytes had little effect on both yield and selectivity for the elec-
trochemical reaction, Et4NBr was slightly better than other bromide
salts (entries 1 and 5–7). On the other hand, use of either Et4NCl or
Et4NI did not yield the oxidation product (entries 8 and 9).
OH
O
OH
-[e]
Pt electrodes, 2 F/mol, 0 °C
+
OH
OH
OH
Et4NBr (1.0 equiv)
MeOH
Ph
1
Ph
2
Ph
recovered 1
ð3Þ
in the presence of Cu(OTf)2 (0.1 equiv) and
(R,R)-Ph-BOX (0.1 equiv)
in the presence of Cu(OTf)2 (0.1 equiv)
in the absence of Cu(OTf)2 and (R,R)-Ph-BOX
36%
58%
88%
100%
3%
0%
-[e]
OH
OH
OH
OH
O
Pt electrodes, 2 F/mol, 0 °C
electrolyte (1.0 equiv)
+
ð4Þ
2.2. Effects of electrolytes and solvents on asymmetric
oxidation
OH
solvent (5 mL)
Ph
Ph
Ph
Cu(OTf)2 (0.1 equiv)
1
(R,R)-1
(S)-2
(
R,R)-Ph-BOX (0.1 equiv)
0.5 mmol
Next, we investigated electrolytes and solvents for the electro-
chemical oxidation that is applicable to kinetic resolution of cis-1
(Eq. 4). The results are summarized in Table 1. A procedure for
asymmetric electrochemical oxidation of cis-1 is as follows: anodic
oxidation of 1 was carried out using platinum electrodes (2ꢁ1 cm2)
in an undivided beaker-type cell containing 0.5 mmol of 1, 1.0 equiv
of electrolyte, 0.1 equiv of Cu(OTf)2, 0.1 equiv of (R,R)-Ph-BOX, and
2.3. Asymmetric oxidation of several cis-cycloalkane-1,2-
diols
Asymmetric electrochemical oxidation of several cis-cyclo-
alkane-1,2-diol derivatives 3-8 is summarized in Table 2 (Eq. 5).10
The s values of (S)-9–11 varied significantly depending on the ring
size (entries 1–3 in Table 2 and entry1 in Table 1). That is, the larger
the ring size, the better the s value obtained. R substituent also
influenced the s value (entries 4–6). Compound 8 with a cyclohexyl
Table 1
Effect of electrolyte and solvent on electrochemical oxidation of 1
Entry
Electrolyte
Solvent
(S)-2
(R,R)-1
s
Table 2
Yield (%)
ee (%)
Yield (%)
ee (%)
Electrochemical oxidation of cis-cycloalkane-1,2-diols 3–8
1
2a
3
4
5
6
7
8
9
Et4NBr
Et4NBr
Et4NBr
Et4NBr
Me4NBr
n-Pr4NBr
n-Bu4NBr
Et4NCl
MeOH
MeOH
MeCN
CH2Cl2
MeOH
MeOH
MeOH
MeOH
MeOH
36
33
Trace
8
28
26
31
Trace
0
67
66
d
13
60
67
59
d
d
58
62
91
79
67
62
63
94
41
36
d
2
28
33
41
d
d
8
7
d
Entry Diol
n
R
(S)-Ketoalocohol
(R,R)-Diol
s
Yield (%) ee (%) Yield (%) ee (%)
1
5
7
6
d
1
2
3
4
5
6
3
4
5
6
7
8
1
3
4
2
2
2
Ph
Ph
Ph
Bn
i-Pr
9
33
38
64
80
5
75
81
59
42
48
35
74
76
22
85
80
47
25
18
3
10 57
11 49
12 65
13 26
12
22
2
9
11
Et4NI
Quant
d
Cyclohexyl 14 21
a
CuBr2 (0.1 equiv) was used instead of Cu(OTf)2 (0.1 equiv).

D. Minato et al. / Tetrahedron 64 (2008) 6675–6683
6677
group was asymmetrically oxidized to afford (S)-14 in higher
selectivity (s¼11, entry 6) than (S)-12 with a benzyl group (s¼2,
entry 6) and (S)-13 with an isopropyl group (s¼9, entry 5).
summarized in Table 3. In the oxidation of racemic N-benzoylpi-
peridinemethanol (24),13 optically active
-aminoester (R)-28 was
a
obtained with low yield but with good enantioselectivity (6% yield,
71% ee) after passing through 5 F/mol14 of electricity (entry 1). The
oxidation of racemic N-benzoylated cyclic and acyclic amino-
alcohols 25–27 afforded the corresponding (R)-aminoesters (R)-
29–31 (entries 2–4) with low electron efficiencies.
-[e]
OH
OH
O
OH
Pt electrodes, 2 F/mol, 0 °C
Et4NBr (1.0 equiv)
+
( )n
R
3-8
( )n
( )n
ð5Þ
OH
OH
MeOH
Cu(OTf)2 (0.1 equiv)
(R,R)-Ph-BOX (0.1 equiv)
R
R
-[e]
(S)-9-14
(R,R)-3-8
R4
R4
R4
Pt electrodes, rt
R3
R3
R3
OH
Et4NBr (1.0 equiv)
OH
N
Bz
+
COOMe
N
Bz
N
Bz
MeOH
Cu(OTf)2 (0.1 equiv)
2.4. Oxidative kinetic resolution of piperidine-3,4-diols
(
R,R)-Ph-BOX (0.1 equiv)
racemic-24-27
(R)-28-31
(S)-24-27
This electrochemical method, interestingly, was applicable to
kinetic resolution of some piperidine-3,4-diols 15, 18, and 22 (Eqs.
6–8),11 which were not oxidized with NBS.3 The electrochemical
oxidation of 15 afforded optically active ketoalcohol (R)-17 and
(3S,4R)-15 in 49% ee and 41% ee, respectively, while 16 was not
obtained (Eq. 6). The loss in the total yield (82%) in the reaction of
15 might be explained by the instability of 3-ketopiperidines under
the oxidative conditions.12 In fact, the oxidation of 18 afforded
(3S,4S)-18 in moderate enantioselectivity along with a small
amount of further oxidized products 20 and 21 instead of 19 (Eq. 7).
On the other hand, oxidation of 22 gave (R)-23 and (3S,4R)-22 with
little loss in the total yield (Eq. 8).
ð9Þ
Since further improvement of the electron efficiency and yield
was difficult, we tried oxidative kinetic resolution of racemic
N-benzoylaminoaldehydes (32–35) (Eq. 10), which might be in-
termediates for the oxidation of aminoalcohols to aminoesters. The
results are shown in Table 4. The oxidation of 32 proceeded more
efficiently than that of aminoalcohol 24 to afford (R)-28 with im-
proved yield and good enantioselectivity after passing through
2.5 F/mol14 of electricity (entry 1). Also, the oxidation of several
aminoaldehydes (33–35) proceeded to afford (R)-29–31 with im-
proved yields and good enantioselectivities (entries 2–4).
OH
OH
O
OH
-[e]
OH
O
OH
OH
Pt electrodes, 2 F/mol, 0 °C
Et4NBr (1.0 equiv)
+
+
N
Ts
15
N
Ts
16
N
Ts
(R)-17
N
Ts
MeOH
ð6Þ
Cu(OTf)2 (0.1 equiv)
(R,R)-Ph-BOX (0.1 equiv)
s=4
(3S,4R)-15
0 %yield
-
33% yield
49% ee
49% yield
41% ee
OH
OH
OH
-[e]
-[e]
Ph
Ph
Ph
OH
O
OH
R4
Pt electrodes, 2 F/mol, 0 °C
Et4NBr (1.0 equiv)
R4
Pt electrodes, rt
Et4NBr (1.0 equiv)
R4
R3
R3
R3
+
N
Bz
CHO
+
COOMe
N
N
Boc
18
N
Boc
19
N
Boc
(3S,4S)-18
45% yield
55% ee
N
CHO
MeOH
MeOH
Cu(OTf)2 (0.1 equiv)
(R,R)-Ph-BOX (0.1 equiv)
Cu(OTf)2 (0.1 equiv)
Bz
Bz
(R,R)-Ph-BOX (0.1 equiv)
racemic-32-35
(R)-28-31
(S)-32-35
0% yield
-
ð10Þ
O
O
Ph
Ph
CO2Me
2.6. Oxidation potentials
+
+
CHO
N
N
Boc
20
Boc
21
Oxidation potentials of materials used in these oxidations are
given in Table 5. The most oxidizable species was Brꢀ, while
Cu(OTf)2 was hardly oxidizable (entries 1 and 2). Although oxida-
tion potential of (R,R)-Ph-BOX was moderate, Cu(OTf)2–(R,R)-Ph-
BOX complex was stable under the oxidative conditions (entries 3
and 4). Diol cis-1 formed a complex with Cu(OTf)2–(R,R)-Ph-BOX,
which was more oxidizable (entries 5 and 6). Similar tendencies
were observed for aminoalcohol 24 and aminoaldehyde 32(entries
9–12). On the other hand, such negative shifts were not observed in
the oxidation potentials of ketoalcohol 2 and aminoester 28 (en-
tries 7, 8, 13, and 14). Among these complexes, cis-1–Cu(OTf)2–
(R,R)-Ph-BOX and 32–Cu(OTf)2–(R,R)-Ph-BOX complexes had the
lowest oxidation potentials (entries 6 and 12).
ð7Þ
OH
O
N
OH
-[e]
OH
Et
OH
Et
Pt electrodes, 2 F/mol, 0 °C
Et4NBr (1.0 equiv)
OH
Et
+
N
Ts
MeOH
Cu(OTf)2 (0.1 equiv)
(R,R)-Ph-BOX (0.1 equiv)
N
Ts
Ts
22
(R)-23
(3S,4R)-22
s=4
61% yield
31% ee
38% yield
39% ee
ð8Þ
2.7. Reaction mechanism for the asymmetric electrochemical
oxidation of aminoalcohols and aminoaldehydes
2.5. Oxidative kinetic resolution of racemic aminoalcohols
and aminoaldehydes
On the basis of oxidation potentials described above, mecha-
nisms for asymmetric electrochemical oxidation of aminoalcohols
G0 and aminoaldehydes H0 are presented in Schemes 2 and 3,
Kinetic resolution of some racemic aminoalcohols 24–27 by
electrochemical oxidation was tested (Eq. 9). The results are

6678
D. Minato et al. / Tetrahedron 64 (2008) 6675–6683
Table 3
Electrochemical oxidation of racemic aminoalcohols 24–27
Entry
racemic
Aminoalcohols
Electricity
(F/mol)
Product (R)-28–31
Yield (%) [ee (%)]
Recovered (S)-24–27
Yield (%) [ee (%)]
OH
N
OH
N
1
2
3
5
3
5
6 [71]
85 [2]
N
Bz
COOMe
Bz
Bz
(R)-28
(S)-24
24
OH
N
OH
N
COOMe
27 [70]
50 [15]
N
Bz
Bz
Bz
(R)-29
O
(S)-25
25
OH
OH
NH
OMe
27 [59]
60 [6]
NH
Bz
Bz
NH
26
(S)-26
Bz
(R)-30
O
OH
NH
OH
NH
4
10
13 [22]
88 [0]
OMe
NH
Bz
Bz
(S)-27
Bz
(R)-31
27
Table 4
R4
Br+
2e
Br-
Electrochemical oxidation of racemic aminoaldehydes 32–35
R3
OH
Entry racemic Electricity (R)-Amino- Yield (%) (S)-Amino- Yield (%)
N
G'
R4
Aminoalcohols (F/mol)
esters
[ee (%)]
19 [87]
aldehydes [ee (%)]a
Bz
anode
R3
Cu2+
N
O
R4
H
1
2.5
(R)-28
(S)-32
66 [12]
Cu2+
Bz
N
CHO
32
R3
L*
I'
* CHO
N
Bz
L*
Bz
L*: (R,R)-Ph-BOX
H'
MeO-
MeOH + Br-
CHO
2
3
2
(R)-29
(R)-30
43 [86]
50 [61]
(S)-33
(S)-34
34 [27]
18 [18]
N
Bz
R4
33
R4
MeOH
MeO-
CHO
R3
R3
1.5
N
O
Br
-
O
Cu2+
N
NH
2MeOH 2MeO- + H2
Cu2+
Bz
Bz
34
Bz
CHO
Br+
L*
L*
J'
4
1.5
(R)-31
18 [64]
(S)-35
65 [12]
2e
cathode
K'
NH
Bz
35
Scheme 2.
a
Determined after transformation of (S)-32–35 to (S)-24–27, respectively.
R4
Table 5
Oxidation potentials
Br+
2e
Br-
R3
CHO
H'
N
Entry
Material
Oxidation potential (V)a
R4
Bz
anode
1
2
3
4
5
6
7
8
Et4NBr
Cu(OTf)2
(R,R)-Ph-BOX
Cu(OTf)2–(R,R)-Ph-BOX complex
Diol cis-1
cis-1–Cu(OTf)2–(R,R)-Ph-BOX complex
Ketoalcohol 2
2–Cu(OTf)2–(R,R)-Ph-BOX complex
Aminoalcohol 24
24–Cu(OTf)2–(R,R)-Ph-BOX complex
Aminoaldehyde 32
32–Cu(OTf)2–(R,R)-Ph-BOX complex
Aminoester 28
1.15
>3.0
2.07
>3.0
2.10
1.80
2.20
2.35
2.20
2.10
2.10
1.75
2.32
2.65
H
R3
Cu2+
L*
N
O
R4
Cu2+
Bz
R3
M'
* COOMe
N
L*
Bz
L*: (R,R)-Ph-BOX
P'
MeO-
MeOH + Br-
9
R4
R4
OMe
MeO-
OMe
10
11
12
13
14
R3
R3
-
O
Cu2+
N
N
O
Br
2MeOH 2MeO- + H2
Bz
Cu2+
Bz
28–Cu(OTf)2–(R,R)-Ph-BOX complex
Br+
L*
L*
O'
a
2e
cathode
V versus Ag/AgNO3.
N'
Scheme 3.
respectively. The electrochemical oxidation of G0 and H0 might
proceed in a manner similar to that of diols as shown in Scheme 1.
Anodically generated Brþ and cathodically generated 2MeOꢀ react
with complexes I0 and/or M0 to afford the corresponding optically
active esters P0.
Although the activated intermediates (R,R)-1-complex and (S)-32-
complex might be formed more easily than (S,S)-1-complex and
(R)-32-complex, MeOꢀ as a base predominantly approaches the
less crowded intermediate (S,S)-1-complex and (R)-32-complex to
afford (S)-2 and (R)-28.
The stereochemical courses for kinetic resolution of cis-1 and 32
catalyzed by Cu(II)–(R,R)-Ph-BOX are shown in Schemes 4 and 5.

D. Minato et al. / Tetrahedron 64 (2008) 6675–6683
6679
(R,R)-Ph-BOX, Cu(OTf)2, Me4NBr, Et4NBr, n-Pr4NBr, n-Bu4NBr,
Et4NCl, and Et4NI were commercially available.
Br+
O
-OMe
O
4.2. Measurement of oxidation potentials
O
Br+
N
N
O
Cu
N
O
BAS CV-50W was used as a voltammetric analyzer. A solution
of substrate (0.1 mmol) in MeCN (10 mL) containing 0.1 M Et4NBF4
was measured. Reference electrode was Ag/AgNO3 in saturated
aqueous KCl, working electrode was a glassy carbon, and counter
electrode was a platinum wire. Scan rate was 100 mV/s.
N
O
R
Cu
H
O
O
H
S
(S,S)-1-complex
(R,R)-1-complex
-OMe
4.3. Preparation of cis-cycloalkane-1,2-diols 3–8
OsO4 (4%, 0.098 mmol) was added to a stirring solution of 1-
phenylcyclohexene (32 mmol, 5.0 g) and 50% N-methylmorpho-
line-N-oxide (35.4 mmol) in THF/acetone/H2O (1/1/1, 180 mL) at
0 ꢂC. After stirring for 16 h, satd aqueous NaHSO3 (120 mL) was
added to the resulting mixture and the solution stirred for 1 h. The
solution was evaporated in vacuo to give the residue, which was
then dissolved in AcOEt. The organic portion was extracted with
AcOEt and dried over MgSO4. The resulting solution was concen-
trated in vacuo. The residue was chromatographed on silica gel
(hexane/AcOEt¼5/1) to afford 1 (93% yield).
O
Ph
OH
O
OH
Ph
(R)-2
(S)-2
Scheme 4. Plausible stereochemical course for kinetic resolution of cis-1.
-OMe
Br+
4.4. Asymmetric electrochemical oxidation of 1: a typical
procedure
Br+
O
O
N
O
N
O
N
N
O
O
Cu
Under an aerobic atmosphere, into an undivided electrolysis cell
equipped with a platinum anode and cathode (1 cmꢁ2 cm) was
added a solution of Cu(OTf)2 (18.1 mg, 0.05 mmol) and (R,R)-Ph-
BOX (16.7 mg, 0.05 mmol) in MeOH (5 mL). This solution was
stirred for 10 min. Into the solution were added 1-phenyl-
cyclohexane-cis-1,2-diol (1, 96.1 mg, 0.5 mmol) and tetraethyl-
ammonium bromide (105.1 mg, 0.5 mmol), and 2 F/mol of
electricity was passed at a constant rate of 50 mA (terminal voltage:
ca. 10 V) through the solution as it was cooled with ice-water. The
solvent was evaporated in vacuo to give the residue, which was
then dissolved in AcOEt. The solution was poured into satd aqueous
Na2S2O3 (5 mL). The organic portion was extracted with AcOEt
(10 mLꢁ3) and dried over MgSO4. The resulting solution was con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (n-hexane/AcOEt¼10:1) to afford (S)-2-hydroxy-
2-phenylcyclohexanone (2) as a white solid and recovered (1R,2R)-
1-phenylcyclohexane-cis-1,2-diol (1) as a white solid.
Cu
H
H
N
N
OMe
O
H
O
H
MeO
(S)-32-complex
(R)-32-complex
-OMe
N
CO2Me
N
CO2Me
Bz
(S)-28
Bz
(R)-28
Scheme 5. Plausible stereochemical course for kinetic resolution of racemic-32 in
MeOH.
3. Conclusion
In conclusion, this article describes an efficient procedure for the
kinetic resolution of racemic cis-cycloalkane-1,2-diols, amino-
alcohols, and aminoaldehydes in the presence of copper(II) triflate
and (R,R)-Ph-BOX by electrochemical oxidation. Further study to
improve the enantioselectivity is underway.
4.4.1. (S)-2-Hydroxy-2-phenylcyclohexanone (2)
29
White solid; mp 74 ꢂC; [
a
]
þ119.3 (c 1.2, CHCl3, 67% ee); IR
D
(neat)
CDCl3)
n
3474, 2944, 2867, 1717, 1451, 1101 cmꢀ1; 1H NMR (300 MHz,
1.62–1.95 (m, 4H), 2.00–2.10 (m, 1H), 2.38–2.60 (m, 2H),
d
2.95–3.05 (m, 1H), 4.50 (s, 1H), 7.26–7.42 (m, 5H); HR-EI (Mþ) calcd
for C12H14O2 190.0994, found 190.0972. The ee was determined by
DAICEL Chiralcel OJ-H (4.6 mmø, 250 mm) [n-hexane/isopropanol
(10/1) (v/v), 1.0 mL/min, detection at 210 nm, 15 min for (R)-2 and
19 min for (S)-2].
4. Experimental section
4.1. General
Electrochemical reactions were carried out by using DC Power
Supply (GP 050-2) of Takasago Seisakusho, Inc. HPLC analyses were
achieved by using an LC-10AT VP and an SPD-10A VP of Shimadzu
Seisakusho Inc. Specific rotations were measured with Jasco DIP-
1000. 1H and 13C NMR spectra were measured at 300 (or 400) and
75 (or 100) MHz on a Varian Gemini 300 spectrometer (or JEOL
JNM-AL 400) with TMS as an internal standard. All melting points
were measured on MICRO MELTING POINT APPARATUS (Yanaco)
and are uncorrected. IR spectra were obtained on a Shimadzu FTIR-
8100A. Mass spectra were obtained on a JEOL JMS-DX 303
instrument.
4.4.2. (1R,2R)-1-Phenylcyclohexane-cis-1,2-diol (1)15
25
White solid; mp 90 ꢂC (lit.15 mp 121–122 ꢂC); [
a
]
ꢀ3.7 (c 1.2,
D
EtOH, 41% ee); 1H NMR (300 MHz, CDCl3)
d 1.35–1.95 (m, 9H), 2.62 (s,
1H), 3.92–4.04 (m, 1H), 7.22–7.28 (m, 1H), 7.38 (t, J¼7.8 Hz, 2H), 7.51
(d, J¼7.2 Hz, 2H). The ee was determined by DAICEL Chiralcel OJ-H
(4.6 mmø, 250 mm) [n-hexane/isopropanol (10/1) (v/v),1.0 mL/min,
detection at 210 nm, 10 min for (1S,2S)-1 and 13 min for (1R,2R)-1].
4.4.3. (S)-2-Hydroxy-2-phenylcyclopentanone (9)
18
Light-yellow oil (lit. 16 for racemate, mp 67 ꢂC); [
a
]
þ57.4 (c
D
1.9, CHCl3, 38% ee); 1H NMR (300 MHz, CDCl3)
d 1.79–1.94 (m, 1H),

6680
D. Minato et al. / Tetrahedron 64 (2008) 6675–6683
2.00–2.16 (m, 1H), 2.16–2.31 (m, 1H), 2.40–2.58 (m, 3H), 2.88 (s,1H),
7.27–7.46 (m, 5H). The ee was determined by DAICEL Chiralcel OJ-H
(4.6 mmø, 250 mm) [n-hexane/isopropanol (10/1) (v/v), 1.0 mL/
min, detection at 210 nm, 16 min for (R)-9 and 20 min for (S)-9].
(m, 2H), 2.50–2.60 (m, 1H), 2.70 (dt, J¼6.0, 13.5 Hz, 1H), 2.97 (d,
J¼13.7 Hz, 1H), 3.14 (d, J¼13.7 Hz, 1H), 3.85 (s, 1H), 7.18–7.36 (m,
5H). The ee was determined by DAICEL Chiralpak AD (4.6 mmø,
250 mm) [n-hexane/isopropanol (10/1) (v/v), 1.0 mL/min, detection
at 254 nm, 9 min for (S)-12 and 11 min for (R)-12].
4.4.4. (1R,2R)-1-Phenylcyclopentane-cis-1,2-diol (3) (lit. 17 for
racemate)
4.4.10. (1R,2R)-1-Benzylcyclohexane-cis-1,2-diol (6)
29
White solid; mp 62–63 ꢂC; [
a]
ꢀ7.2 (c 3.2, CHCl3, 22% ee); IR
White solid; mp 103–104 ꢂC (lit. 20 for racemate, mp 107–
D
29
(neat)
n
3400, 2967, 1447, 1092, 1055, 758, 700 cmꢀ1
;
1H NMR
108 ꢂC); [
a
]
ꢀ0.3 (c 1.0, CHCl3, 47% ee); IR (neat)
n 3404,
D
(300 MHz, CDCl3)
d
1.60–1.86 (m, 2H), 1.86–2.16 (m, 4H), 2.30 (br s,
2938 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 1.16–1.92 (m, 8H), 2.85 (d,
1H), 2.80 (br s, 1H), 4.22 (t, J¼7.5 Hz, 1H), 7.15–7.28 (m, 1H), 7.33 (t,
J¼7.5 Hz, 2H), 7.45 (d, 2H). The ee was determined by DAICEL
Chiralcel OJ-H (4.6 mmø, 250 mm) [n-hexane/isopropanol (10/1)
(v/v), 1.0 mL/min, detection at 210 nm, 15 min for (1S,2S)-3 and
19 min for (1R,2R)-3].
J¼13.5 Hz, 2H), 2.95 (d, J¼13.5 Hz, 2H), 3.40–3.50 (m, 1H), 7.20–7.35
(m, 5H). The ee was determined by DAICEL Chiralcel OJ-H
(4.6 mmø, 250 mm) [n-hexane/isopropanol (10/1) (v/v), 1.0 mL/
min, detection at 210 nm, 9 min for (1S,2S)-6 and 11 min for
(1R,2R)-6].
4.4.5. (S)-2-Hydroxy-2-phenylcycloheptanone (10) (lit. 18 for
4.4.11. (S)-2-Hydroxy-2-isopropylcyclohexanone (13) (lit. 21 for
racemate)
Light-yellow oil; [
(300 MHz, CDCl3)
(m, 2H), 2.40–2.55 (m, 1H), 2.75–2.88 (m, 1H), 4.58 (s, 1H), 7.25–
7.40 (m, 3H), 7.40–7.50 (m, 2H). The ee was determined by DAICEL
Chiralcel OJ-H (4.6 mmø, 250 mm) [n-hexane/isopropanol (10/1)
(v/v),1.0 mL/min, detection at 210 nm, 20 min for (S)-10 and 30 min
for (R)-10].
racemate)
Colorless oil; [
(300 MHz, CDCl3)
1.55–1.80 (m, 4H), 2.06–2.18 (m, 1H), 2.18–2.32 (m, 1H), 2.32–2.43
(m, 1H), 2.43–2.53 (m, 2H), 3.81 (s, 1H). The ee was determined by
DAICEL Chiralpak AS (4.6 mmø, 250 mm) [n-hexane/isopropanol
(80/1) (v/v), 1.0 mL/min, detection at 210 nm, 6.5 min for (S)-13 and
7.5 min for (R)-13].
29
29
a
]
þ123.4 (c 1.7, CHCl3, 64% ee); 1H NMR
a
d
]
þ44.1 (c 0.4, CHCl3, 75% ee); 1H NMR
D
D
d
1.22–1.68 (m, 3H), 1.83–2.10 (m, 3H), 2.22–2.40
0.70 (d, J¼6.9 Hz, 3H), 1.01 (d, J¼6.6 Hz, 3H),
4.4.6. (1R,2R)-1-Phenylcycloheptane-cis-1,2-diol (4)
4.4.12. (1R,2R)-1-Isopropylcyclohexane-cis-1,2-diol (7)
28
White solid; mp 99–100 ꢂC; [
a
]
ꢀ1.9 (c 1.0, CHCl3, 85% ee); IR
White solid; mp 91–92 ꢂC; IR (neat)
n 3400, 2940, 1449,
D
(neat)
CDCl3)
n
3400, 3023, 2930, 1460, 1019 cmꢀ1
;
1H NMR (400 MHz,
1071 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
0.91 (d, J¼7.5 Hz, 3H), 0.94
d
1.40–1.78 (m, 7H), 1.78–2.15 (m, 4H), 2.90 (s, 1H), 4.00 (d,
(d, J¼7.5 Hz, 3H), 1.12–1.30 (m, 3H), 1.40–1.80 (m, 7H), 2.08 (sep,
J¼10.4 Hz, 1H), 7.22–7.32 (m, 1H), 7.32–7.47 (m, 2H), 7.47–7.64 (m,
J¼7.1 Hz, 1H), 3.66 (dd, J¼4.2, 9.0 Hz, 1H); 13C NMR (100 MHz,
2H); 13C NMR (100 MHz, CDCl3)
d
20.0, 22.7, 26.6, 29.8, 39.1, 77.5,
CDCl3) d
16.2, 17.6, 20.6, 23.6, 28.0, 30.6, 32.8, 71.0, 75.4; HR-EI (Mþ)
78.9, 124.8, 126.9, 128.5, 148.3; HR-EI (Mþ) calcd for C13H18O2
206.1307, found 206.1300. The ee was determined by DAICEL
Chiralcel OJ-H (4.6 mmø, 250 mm) [n-hexane/isopropanol (10/1)
(v/v), 1.0 mL/min, detection at 210 nm, 11 min for (1S,2S)-4 and
13 min for (1R,2R)-4].
calcd for C9H18O2 158.1307, found 158.1267. The ee of the 1-iso-
propylcyclohexane-cis-1,2-diol (7) was determined by HPLC of the
corresponding 2-phenylcarbamoylated compound 70 by usual
method.
4.4.13. (1R,2R)-1-Hydroxy-1-isopropyl-2-phenylcarbamoyl-
4.4.7. (S)-2-Hydroxy-2-phenylcyclooctanone (11)
oxycyclohexane (70)
29
27
Colorless oil; [
a
]
þ177.7 (c 2.0, CHCl3, 80% ee); IR (neat)
n
3467,
1H NMR
0.96–1.12 (m, 1H), 1.35–1.62 (m, 2H), 1.62–2.04
Light-yellow oil; [
a]
þ1.8 (c 1.0, CHCl3, 25% ee); IR (neat)
n
3300,
D
D
2930, 2859, 1701, 1698, 1466, 1447, 1364, 1127 cmꢀ1
(300 MHz, CDCl3)
;
2942, 2867, 1707, 1601, 1545, 1231, 1061 cmꢀ1
CDCl3)
;
1H NMR (300 MHz,
d
d
0.92 (d, J¼7.2 Hz, 3H), 0.96 (d, J¼7.2 Hz, 3H), 1.22–1.41 (m,
(m, 5H), 2.04–2.16 (m, 1H), 2.16–2.28 (m, 1H), 2.70–2.88 (m, 1H),
2H),1.41–2.00 (m, 8H), 4.91 (dd, J¼5.1,10.2 Hz,1H), 6.75 (s, 1H), 7.07
2.88–3.02 (m, 1H), 4.81 (s, 1H), 7.25–7.40 (m, 3H), 7.48 (d, J¼6.9 Hz,
(t, J¼6.9 Hz, 1H), 7.22–7.45 (m, 4H); 13C NMR (100 MHz, CDCl3)
2H); 13C NMR (100 MHz, CDCl3)
d
22.6, 24.2, 25.3, 30.1, 31.3, 36.0,
d 16.1, 17.5, 20.3, 23.7, 27.5, 28.5, 33.7, 75.2, 25.3, 118.5, 123.4, 129.0,
81.0, 126.0, 127.9, 128.5, 141.4, 216.6; HR-EI (Mþ) calcd for C14H18O2
218.1307, found 218.1302. The ee was determined by DAICEL Chir-
alcel OJ-H (4.6 mmø, 250 mm) [n-hexane/isopropanol (10/1) (v/v),
1.0 mL/min, detection at 210 nm, 20 min for (S)-11 and 28 min for
(R)-11].
137.9, 152.8; HR-EI (Mþ) calcd for C16H23NO3 277.1678, found
277.1677. The ee was determined by DAICEL Chiralpak AS (4.6 mmø,
250 mm) [n-hexane/isopropanol (50/1) (v/v), 1.0 mL/min, detection
at 254 nm, 16 min for (1S,2S)-70 and 19 min for (1R,2R)-70].
4.4.14. (S)-2-Hydroxy-2-cyclohexylcyclohexanone (14)
29
4.4.8. (1R,2R)-1-Phenylcyclooctane-cis-1,2-diol (5)
Light-yellow oil (lit. 21 for racemate, mp 46–46.5 ꢂC); [
a]
D
29
White solid; mp 46–47 ꢂC; [
a]
ꢀ8.3 (c 1.2, CHCl3, 80% ee); IR
þ91.9 (c 1.2, CHCl3, 81% ee); 1H NMR (300 MHz, CDCl3)
d 1.00–1.48
D
(neat)
n
3400, 2923, 1601, 1447, 1028, 702 cmꢀ1; 1H NMR (300 MHz,
1.20–1.92 (m, 11H), 2.00–2.15 (m, 1H), 2.24–2.40 (m, 1H),
(m, 7H), 1.55–2.06 (m, 8H), 2.06–2.18 (m, 1H), 2.36–2.57 (m, 3H),
3.85 (s, 1H). The ee was determined by DAICEL Chiralpak AD
(4.6 mmø, 250 mm) [n-hexane/isopropanol (40/1) (v/v), 1.0 mL/
min, detection at 210 nm, 8 min for (S)-14 and 11 min for (R)-14].
CDCl3)
d
2.98 (s, 1H), 4.40 (dd, J¼3.0, 8.7 Hz, 1H), 7.22–7.32 (m, 1H), 7.39 (t,
J¼7.8 Hz, 2H), 7.54 (d, J¼6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
21.3, 24.2, 26.8, 28.1, 30.8, 36.5, 75.6, 78.3, 125.4, 127.0, 128.4,
146.4; HR-EI (Mþ) calcd for C14H20O2 220.1554, found 220.1454. The
ee was determined by DAICEL Chiralpak AS (4.6 mmø, 250 mm) [n-
hexane/isopropanol (10/1) (v/v), 1.0 mL/min, detection at 210 nm,
7 min for (1S,2S)-5 and 13 min for (1R,2R)-5].
4.4.15. (1R,2R)-1-Cyclohexylcyclohexane-cis-1,2-diol (8)
White solid; mp 109–110 ꢂC; IR (neat)
n
3400, 2928, 1445,
0.95–1.90 (m, 21H), 3.60–
20.8, 23.7, 26.7, 26.9, 27.8,
1075 cmꢀ1; 1H NMR (300 MHz, CDCl3)
3.70 (m,1H); 13C NMR (100 MHz, CDCl3)
d
d
29.5, 30.6, 43.6, 70.7, 75.2; HR-EI (Mþ) calcd for C12H22O3 198.1620,
found 198.1592. The ee of the 1-cyclohexylcyclohexane-cis-1,2-diol
(8) was determined by HPLC of the corresponding 2-phenyl-
carbamoylated compound 80.
4.4.9. (S)-2-Hydroxy-2-benzylcyclohexanone (12)19
29
White solid; mp 55 ꢂC; [
(300 MHz, CDCl3)
a
]
þ6.3 (c 1.7, CHCl3, 5% ee); 1H NMR
D
d 1.60–1.80 (m, 2H), 1.80–1.95 (m, 2H), 2.14–2.47

D. Minato et al. / Tetrahedron 64 (2008) 6675–6683
6681
4.4.16. (1R,2R)-1-Hydroxy-1-cyclohexyl-2-phenylcarbamoyl-
(100 MHz, CDCl3)
d
28.2, 38.0, 44.4, 51.2, 51.9, 80.4, 128.1, 128.6,
oxycyclohexane (80)
133.2, 136.7, 155.2, 170.9, 199.2; HR-EI (Mþ) calcd for C17H23NO5
321.1576, found 321.1571.
29
White solid; mp 125 ꢂC; [
a]
þ3.5 (c 2.5, CHCl3, 18% ee); IR
D
(neat)
1H NMR (300 MHz, CDCl3)
10.2 Hz, 1H), 6.76 (s, 1H), 7.07 (t, J¼7.2 Hz, 1H), 7.28–7.43 (m, 4H);
13C NMR (100 MHz, CDCl3)
20.5, 23.7, 26.1, 26.6, 26.8, 26.9, 27.4,
n ;
3308, 2938, 2855, 1736, 1608, 1549, 1447, 1325, 1237 cmꢀ1
d
0.90–1.90 (m, 20H), 4.89 (dd, J¼4.8,
4.4.22. (R)-3-Ethyl-3-hydroxy-N-(p-tolylsulfonyl)piperidine-
4-one (23)
27
d
White solid; mp 85–87 ꢂC; [
a]
ꢀ11.2 (c 1.0, CHCl3, 31% ee); IR
D
27.7, 30.2, 44.6, 75.0, 75.1, 118.5, 123.4, 129.1, 137.9, 152.7; HR-EI
(Mþ) calcd for C19H27NO3 317.1991, found 317.2000. The ee was
determined by DAICEL Chiralpak AD (4.6 mmø, 250 mm) [n-hex-
ane/isopropanol (10/1) (v/v), 1.0 mL/min, detection at 210 nm,
9 min for (1R,2R)-80 and 12 min for (1S,2S)-80].
(neat) n ;
2855, 1718, 1339, 1157 cmꢀ1 1H NMR (400 MHz, CDCl3)
d
0.87 (t, J¼7.6 Hz, 3H),1.85–2.00 (m,1H), 2.00–2.15 (m,1H), 2.31 (d,
J¼11.6 Hz, 1H), 2.40–2.62 (m, 2H), 2.43 (s, 3H), 2.82–2.97 (m, 1H),
3.72 (s, 1H, –OH), 4.03 (dd, J¼2.8, 12.0 Hz, 1H), 4.08–4.20 (m, 1H),
7.34 (d, J¼8.4 Hz, 2H), 7.65 (d, J¼8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3)
d 6.6, 21.5, 29.5, 37.3, 46.9, 55.8, 78.0, 127.4, 129.9, 133.1,
4.4.17. N-(p-Tolylsulfonyl)piperidine-(3S,4R)-diol (15)
144.2, 209.9; HR-EI (Mþ) calcd for C14H19NO4S 297.1035, found
297.1022. The ee was determined by DAICEL Chiralcel OD-H
(4.6 mmø, 250 mm) [n-hexane/ethanol (20/1) (v/v), 1.0 mL/min,
detection at 210 nm, 18 min for (3S)-23 and 19 min for (3R)-23].
White solid; mp 112 ꢂC (lit. 22 for racemate, mp 138–140 ꢂC);
22
[
a]
ꢀ7.1 (c 1.0, CHCl3, 41% ee); IR (neat)
n
3350, 2926, 2872, 2359,
1.77–1.95
D
1929, 1732, 1661, 1599 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
(m, 2H), 2.08–2.18 (m, 1H), 2.18–2.36 (m, 1H), 2.44 (s, 3H), 2.94–3.10
(m, 3H), 3.10–3.23 (m, 1H), 3.70–3.82 (m, 1H), 3.82–3.94 (m, 1H),
7.33 (d, J¼8.1 Hz, 2H), 7.65 (d, J¼8.1 Hz, 2H); 13C NMR (100 MHz,
4.4.23. N-(p-Tolylsulfonyl)-3-ethylpiperidine-(3S,4R)-diol (22)
28
White solid; mp 98–102 ꢂC; [
a]
D
þ3.6 (c 0.6, CHCl3, 39% ee); IR
CDCl3)
d
21.5, 29.2, 41.9, 42.0, 67.4, 67.7, 127.6, 129.8, 143.8; HR-EI
(neat)n d 0.94
2967,1464,1335,1163 cmꢀ1;1HNMR (400 MHz, CDCl3)
(Mþ) calcd for C12H17NO4S 271.0878, found 271.0876. The ee was
determined by DAICEL Chiralcel OD-H (4.6 mmø, 250 mm) [n-
hexane/ethanol (20/1) (v/v), 1.0 mL/min, detection at 210 nm,
12 min for (3R,4S)-15 and 16 min for (3S,4R)-15].
(t, J¼7.6 Hz, 3H), 1.58–1.80 (m, 2H), 1.70–1.82 (m, 1H), 1.88–2.00 (m,
1H), 2.00–2.40 (m, 2H, –OH), 2.44 (s, 3H), 2.71 (d, J¼11.6 Hz, 1H),
2.70–2.82 (m,1H), 3.11 (d, J¼11.6 Hz,1H), 3.18–3.30 (m1H), 3.35–3.45
(m, 1H), 7.34 (d, J¼8.0 Hz, 2H), 7.64 (d, J¼8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3)
d 7.0, 21.5, 27.7, 29.5, 43.2, 51.0, 70.5, 71.8, 127.6,
4.4.18. (3R)-Hydroxy-N-(p-tolylsulfonyl)piperidine-4-one (17)
129.8, 132.9, 143.8; HR-EI (Mþ) calcd for C14H21NO4S 299.1191, found
299.1181. The ee was determined by DAICEL Chiralcel OD-H
(4.6 mmø, 250 mm) [n-hexane/ethanol (10/1) (v/v), 1.0 mL/min, de-
tection at 210 nm, 19 min for (3R,4S)-22 and 23 min for (3S,4R)-22].
19
Colorless solid; mp 114 ꢂC; [
a
]
D
þ1.1 (c 0.75, CHCl3, 49% ee); IR
(neat)
CDCl3)
n
3350, 2926, 2857, 1732, 1345 cmꢀ1
2.30–2.43 (m, 1H), 2.44 (s, 3H), 2.50–2.90 (m, 3H), 3.53 (br
;
1H NMR (300 MHz,
d
s, 1H), 4.10–4.25 (m, 1H), 4.28–4.45 (m, 2H), 7.35 (d, J¼10.4 Hz, 2H),
7.69 (d, J¼10.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
21.5, 38.7, 46.5,
4.5. A typical procedure for the preparation of racemic
aminoalcohols
52.5, 72.5, 100.6, 127.4, 127.7, 130.0, 133.5, 144.3; HR-EI (Mþ) calcd
for C12H15NO4S 269.0722, found 269.0719. The ee was determined
by DAICEL Chiralcel OJ (4.6 mmø, 250 mm) [n-hexane/isopropanol
(20/1) (v/v), 1.0 mL/min, detection at 210 nm, 9 min for (3S)-17 and
11 min for (3R)-17].
Sodium tetrahydroborate (120 mmol, 4.54 g) and calcium chlo-
ride (60 mmol, 6.66 g) were added to a stirred solution of racemic N-
benzoylalanine methyl ester (racemic-30, 30 mmol, 6.22 g) in THF/
MeOH(4/1,150 mL)at 0 ꢂC. Thereactionmixturewas stirredfor 12 h.
Water (50 mL) was added to the resulting mixture and the solution
stirred for 15 min. The solution was evaporated in vacuo to give
a residue, which was then dissolved in AcOEt. The organic portion
was extracted with AcOEt and dried over MgSO4. The resulting so-
lutionwas concentrated invacuo. Theresiduewas chromatographed
on silica gel (n-hexane/AcOEt¼1/1) to afford 26 (85% yield).
4.4.19. N-(tert-Butoxycarbonyl)-3-phenylpiperidine-(3S,4S)-
diol (18)
22
Colorless solid; mp 101–103 ꢂC; [
a]
ꢀ10.1 (c 0.2, CHCl3, 55% ee);
D
IR (neat)
n
3350, 2976, 2926, 2957, 2855,1750,1694,1671,1466,1377,
;
1167 cmꢀ1
1H NMR (400 MHz, CDCl3)
d
1.48 (s, 9H), 1.85–2.10 (m,
3H), 2.70–2.87 (m,1H), 2.90–3.08 (m, 2H), 3.80–4.30 (m, 3H), 7.28 (t,
J¼7.6 Hz, 1H), 7.38 (t, J¼7.6 Hz, 2H), 7.47 (d, J¼7.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3)
d
28.4, 37.9, 40.0, 44.4, 70.9, 74.3, 79.9, 125.0,
4.6. A typical procedure for the preparation of racemic
aminoaldehydes
127.4, 128.6, 144.8, 154.8; HR-EI (Mþ) calcd for C16H23NO4 293.1627,
found 293.1616. The ee was determined by DAICEL Chiralcel OJ
(4.6 mmø, 250 mm) [n-hexane/ethanol (15/1) (v/v), 1.0 mL/min,
detection at 210 nm, 9 min for (3S,4S)-18 and 11 min for (3R,4R)-18].
To a solution of N-benzoyl-2-(hydroxymethyl)piperidine (race-
mic-24, 10 mmol, 2.19 g) and TEMPO (1 mmol, 156 mg) in CH2Cl2
(10 mL) was added PhI(OAc)2 (11 mmol, 3.54 g). The reaction mix-
ture was stirred for 1 h and then quenched with satd aqueous
Na2S2O3 (5 mL). The organic portion was extracted with CH2Cl2 and
dried over MgSO4. The resulting solution was concentrated in
vacuo. The residue was chromatographed on silica gel (n-hexane/
AcOEt¼2/1) to afford 32 (73% yield).
4.4.20. N-(tert-Butoxycarbonyl)-N-(3-oxo-3-phenylpropyl)-
formamide (20)
Colorless oil; IR (neat)
n
2978, 2932, 2359, 2344, 1740, 1686,
1.53 (s, 9H), 3.25 (t,
1342, 1149 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
J¼7.5 Hz, 2H), 4.05 (t, J¼7.5 Hz, 2H), 7.40–7.50 (m, 2H), 7.50–7.64
(m, 1H), 7.90–8.00 (m, 2H), 9.19 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
28.0, 29.7, 36.6, 36.9, 84.4, 128.1, 128.7, 133.3, 136.5, 163.0, 197.7;
4.6.1. N-Benzoyl-2-piperidinecarbaldehyde (32)23
HR-EI (Mþ) calcd for C15H19NO4 277.1314, found 277.1292.
Colorless oil; 1H NMR (300 MHz, CDCl3)
d 1.30–1.90 (m, 5H),
2.16–2.20 (m,1H), 3.02–3.21 (m,1H), 3.60–3.80 (m,1H), 5.30 (s,1H),
7.43 (m, 5H), 9.66 (s, 1H).
4.4.21. N-(tert-Butoxycarbonyl)-N-(3-oxo-3-phenylpropyl)glycine
methyl ester (21)
Colorless oil; IR (neat)
n
2976, 2359, 1752, 1705, 1682, 1367, 1213,
1.41 and 1.47 (2s, 9H), 3.25–
4.6.2. N-Benzoyl-2-pyrrolidinecarbaldehyde (33)23
1169 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
Colorless oil; 1H NMR (300 MHz, CDCl3)
d 1.81–2.30 (m, 4H),
3.45 (m, 2H), 3.60–3.80 (m, 5H), 4.07 (d, J¼14.4 Hz, 2H), 7.40–7.55
3.50–3.70 (m, 2H), 4.64–4.75 (m, 1H), 7.30–7.45 (m, 3H), 7.50–7.80
(m, 2H), 9.69 (s, 1H).
(m, 2H), 7.50–7.65 (m, 1H), 7.97 (d, J¼8.0 Hz, 2H); 13C NMR

6682
D. Minato et al. / Tetrahedron 64 (2008) 6675–6683
4.6.3. N-(1-Formylethyl)benzamide (34)24
3H), 2.40–2.83 (br s, 1H), 3.60–3.68 (m, 1H), 3.72–3.80 (m, 1H),
Colorless oil; 1H NMR (300 MHz, CDCl3)
d
1.51 (d, J¼7.5 Hz, 3H),
4.322–4.35 (m, 1H), 6.44 (br s, 1H), 7.30–7.56 (m, 3H), 7.70–7.88 (m,
2H). The ee was determined by DAICEL Chiralcel OJ-H (4.6 mmø,
250 mm) [n-hexane/isopropanol (20/1) (v/v), 1.0 mL/min, detection
at 220 nm, 8.3 min for (S)-26 and 9.6 min for (R)-26].
4.70–4.81 (m, 1H), 6.83 (br s, 1H), 7.32–7.58 (m, 3H), 7.81–7.86 (m,
2H), 9.66 (s, 1H).
4.6.4. N-(1-Formyl-2-methylpropyl)benzamide (35)
White solid; mp 68–70 ꢂC; IR (neat)
n
3320, 2967,1732,1647,1536,
4.7.7. Methyl (2R)-(N-benzoyl)amino-3-methylbutyrate (N-
1314 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
1.07 (d, J¼6.9 Hz, 3H),1.09 (d,
benzoyl-D-valine methyl ester) (31)
J¼6.9 Hz, 3H), 2.40–2.52 (m, 1H), 4.82–4.89 (m, 1H), 6.73 (br s, 1H),
White solid; mp 94–96 ꢂC (lit. 30 for racemic form, mp 86 ꢂC);
7.44–7.59 (m, 3H), 7.83 (d, J¼6.9 Hz, 2H), 9.77 (s, 1H); 13C NMR
[a
]
ꢀ33.5 (c 0.5, CHCl3, 64% ee); 1H NMR (300 MHz, CDCl3)
d 0.99
20
D
(100 MHz,CDCl3)
d
17.9,19.0, 24.4, 63.6,127.1,128.6,131.8,140.0,167.6,
(d, J¼7.2 Hz, 3H), 1.03 (d, J¼7.2 Hz, 3H), 2.22–2.35 (m, 1H), 3.78 (s,
3H), 4.78–4.82 (m, 1H), 6.62 (m, 1H), 7.43–7.56 (m, 3H), 7.82 (d,
J¼6.6 Hz, 2H). The ee was obtained by DAICEL Chiralcel OD-H
(4.6 mmø, 250 mm) [n-hexane/isopropanol (50/1) (v/v), 1.0 mL/
min, detection at 254 nm, 15 min for (R)-31 and 20 min for (S)-31].
199.8; HR-EI (Mþ) calcd for C12H15NO2 205.1103, found 205.1098.
4.7. Asymmetric electrochemical oxidation of aminoalcohols
The oxidation was carried out according to the typical experi-
mental procedure for the oxidation of 1.
4.7.8. (2S)-(N-Benzoyl)amino-3-methylbutan-1-ol (27)31
27
White solid; mp 84–85 ꢂC (lit.31 mp 99 ꢂC); [
a
]
ꢀ4.5 (c 1.0,
D
4.7.1. N-Benzoyl-(2R)-(methoxycarbonyl)piperidine (28) (lit. 23 for
CHCl3, 12% ee); 1H NMR (300 MHz, CDCl3)
d
1.00 (d, J¼6.9 Hz, 3H),
racemate)
Colorless oil; [
(300 MHz, CDCl3)
1.02 (d, J¼6.9 Hz, 3H), 1.95–2.06 (m, 1H), 2.90–3.22 (br s, 1H), 3.75–
3.78 (m, 2H), 3.89–3.98 (m, 1H), 6.48 (br s, 1H), 7.39–7.56 (m, 3H),
7.77 (d, J¼6.9 Hz, 2H). The ee was obtained by DAICEL Chiralcel OD-
H (4.6 mmø, 250 mm) [n-hexane/isopropanol (20/1) (v/v), 1.0 mL/
min, detection at 254 nm, 13 min for (S)-27 and 22 min for (R)-27].
26
a
d
]
D
þ51.0 (c 0.40, CHCl3, 87% ee); 1H NMR
1.25–1.82 (m, 5H), 2.26–2.40 (m, 1H), 3.18–3.30
(m, 1H), 3.60–3.70 (m, 1H), 3.79 (s, 3H), 5.50–5.58 (m, 1H), 7.42 (m,
5H). The ee was obtained by DAICEL Chiralcel OD-H (4.6 mmø,
250 mm) [n-hexane/isopropanol (30/1) (v/v), 1.0 mL/min, detection
at 254 nm, 25 min for (R)-28 and 27 min for (S)-28].
Acknowledgements
4.7.2. N-Benzoyl-(2S)-(hydroxymethyl)piperidine (24)4c
We thank JSPS Research Fellowships for Young Scientists, the
Sumitomo Foundation, and a Grant-in-Aid for Young Scientists (B)
(19790017) from the Ministry of Education, Science, Sports, and
Culture, Japan.
26
White solid; mp 89–92 ꢂC (lit. 25for racemate, mp 93–95 ꢂC); [
a]
D
ꢀ7.1 (c 2.0, CHCl3, 12% ee); 1H NMR (300 MHz, CDCl3)
d 1.40–1.90 (m,
6H), 2.80–3.20 (m, 2H), 3.50–3.80 (m,1H), 3.96 (dd, J¼9.9,10.5 Hz,1H),
4.85(brs,1H), 7.41(m, 5H). TheeewasdeterminedbyDAICELChiralcel
OD-H (4.6 mmø, 250 mm) [n-hexane/isopropanol (30/1) (v/v),1.0 mL/
min, detection at 254 nm, 30 min for (S)-24 and 34 min for (R)-24].
References and notes
1. (a) David, S. C.R. Acad. Sci. Paris, Ser. C 1974, 278, 1051–1053; (b) David, S.;
Theffry, A. J. Chem. Soc., Perkin Trans. 1 1979, 1568–1573.
2. Maki, T.; Fukae, K.; Harasawa, H.; Ohishi, T.; Matsumura, Y.; Onomura, O.
Tetrahedron Lett. 1998, 39, 651–654.
3. Onomura, O.; Arimoto, H.; Matsumura, Y.; Demizu, Y. Tetrahedron Lett. 2007, 48,
8668–8672.
4. Some of the asymmetric reactions catalyzed with Cu(II)–Ph-BOX reported by
us, monobenzoylation of 1,2-diols: (a) Matsumura, Y.; Maki, T.; Murakami, S.;
Onomura, O. J. Am. Chem. Soc. 2003, 125, 2052–2053. Monosulfonylation of 1,2-
diols: (b) Demizu, Y.; Matsumoto, K.; Onomura, O.; Matsumura, Y. Tetrahedron
Lett. 2007, 48, 7605–7609. Benzoylation of 1,2-aminoalcohols: (c) Mitsuda, M.;
Tanaka, T.; Tanaka, T.; Demizu, Y.; Onomura, O.; Matsumura, Y. Tetrahedron Lett.
2006, 47, 8073–8077. Tosylation of 2-hydroxyalkanamides: (d) Onomura, O.;
Mitsuda, M.; Nguyen, M. T. T.; Demizu, Y. Tetrahedron Lett. 2007, 48, 9080–9084.
Benzoylation of 3-hydroxyalkanamides: (e) Demizu, Y.; Kubo, Y.; Matsumura,
Y.; Onomura, O. Synlett 2008, 433–437. Alkylation into iminium ions: (f)
Matsumura, Y.; Minato, D.; Onomura, O. J. Organomet. Chem. 2007, 692, 654–
663.
4.7.3. N-Benzoyl-(2R)-methoxycarbonylpyrrolidine (N-Benzoyl-D-
proline methyl ester) (29)
21
White solid; mp 69–72 ꢂC (lit. 26 for -form, mp 89–90 ꢂC); [
L a]
D
þ83.7 (c 0.5, CHCl3, 86% ee); 1H NMR (300 MHz, CDCl3)
d 1.80–2.11
(m, 3H), 2.14–2.40 (m, 1H), 3.50–3.60 (m, 1H), 3.62–3.71 (m, 1H),
3.78 (s, 3H), 4.66–4.70 (m, 1H), 7.30–7.45 (3H), 7.50–7.60 (m, 2H).
The ee was determined by DAICEL Chiralpak AD (4.6 mmø,
250 mm) [n-hexane/isopropanol (20/1) (v/v), 1.0 mL/min, detection
at 254 nm, 30 min for (R)-29 and 39 min for (S)-29].
4.7.4. N-Benzoyl-(2S)-hydroxymethylpyrrolidine (25)27
19
Colorless oil; [
(300 MHz, CDCl3)
a
]
D
ꢀ21.1 (c 1.6, CHCl3, 15% ee); 1H NMR
d
1.57–1.95 (m, 4H), 2.12–2.25 (m, 1H), 3.42–3.58
(m, 2H), 3.70–3.83 (m, 2H), 4.37–4.46 (m, 1H), 4.90–4.98 (m, 1H),
7.38–7.55 (m, 5H). The ee was obtained by DAICEL Chiralpak AD
(4.6 mmø, 250 mm) [n-hexane/isopropanol (20/1) (v/v), 1.0 mL/
min, detection at 254 nm, 30 min for (R)-25 and 36 min for (S)-25].
5. Jakka, K.; Zhao, C.-G. Org. Lett. 2006, 8, 3013–3015.
6. Ladziata, U.; Carlson, J.; Zhdankin, V. V. Tetrahedron Lett. 2006, 47, 6301–6304.
7. Kagan, H. B.; Fiaud, J. C. Topics in Stereochemistry; Eliel, E. L., Ed.; Wiley and
Sons: New York, NY, 1988; Vol. 18, pp 249–330.
8. The absolute stereoconfiguration of recovered (R,R)-1 was determined by
comparing with specific rotation of authentic sample.9
9. Huang, J.; Corey, E. J. Org. Lett. 2003, 5, 3455–3458.
10. Absolute stereoconfigurations of (R,R)-3–8 shown in Eq. 5 and Table 2 were
deduced on the basis of that of (R,R)-1ap.
11. Absolute stereoconfigurations of 15, 17, 18, 22, and 23 shown in Eqs. 6–8 were
deduced on the basis of that of (R,R)-1.
4.7.5. Methyl (2R)-(N-benzoyl)aminopropionate (N-benzoyl-D-
alanine methyl ester) (30)
23
Colorless oil (lit. 28 for
CHCl3, 59% ee) [lit. 28 for
(300 MHz, CDCl3)
L
-form, mp 52–53 ꢂC); [
a]
ꢀ23.3 (c 1.4,
D
23
L
-form, [
a
]
D
þ38.6 (c 2.9, CHCl3)]; 1H NMR
12. Schirmann, P. J.; Matthews, R. S.; Dittmer, D. C. J. Org. Chem. 1983, 48, 4426–
4427.
d
1.53 (d, J¼6.9 Hz, 3H), 3.80 (s, 3H), 4.75–4.83
13. racemic N-Benzyloxycarbonylpiperidinemethanol4c was hardly oxidized under
the reaction conditions.
(m, 1H), 6.74 (br s, 1H), 7.41–7.55 (m, 3H), 7.80–7.85 (m, 2H). The ee
was obtained by DAICEL Chiralcel OJ-H (4.6 mmø, 250 mm) [n-
hexane/isopropanol (20/1) (v/v), 1.0 mL/min, detection at 220 nm,
16 min for (R)-30 and 17 min for (S)-30].
14. Excess amounts of electricity (10–20 F/mol for aminoalcohol 24, 5–10 F/mol for
aminoaldehyde 32) did not improve the yields of aminoester 28.
15. King, S. B.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 5611–5612.
16. Syper, L. Tetrahedron 1987, 43, 2853–2872.
4.7.6. (2S)-(N-Benzoyl)aminopropan-1-ol (26)29
17. Wistuba, E.; Ruechardt, C. Tetrahedron Lett. 1981, 22, 4069–4072.
18. Kise, N.; Agui, S.; Morimoto, S.; Ueda, N. J. Org. Chem. 2005, 70, 9407–9410.
19. Bisel, P.; Lauktien, G.; Weckert, E.; Frahm, A. W. Tetrahedron: Asymmetry 1998, 9,
4027–4034.
26
White solid; mp 110–112 ꢂC (lit.29 mp 132–133 ꢂC); [
a]
ꢀ1.0 (c
D
0.9, CHCl3, 18% ee); 1H NMR (300 MHz, CDCl3)
d
1.28 (d, J¼6.6 Hz,

D. Minato et al. / Tetrahedron 64 (2008) 6675–6683
6683
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49, 3711–3716.
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45, 1900–1903.
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Chem. Pharm. Bull. 1975, 23, 48–53.
27. Takahashi, H.; Kawabata, A.; Higashiyama, K. Chem. Pharm. Bull. 1987, 45, 1604–
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4865–4872.
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´
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