Chiral azabicyclo-N-oxyls mediated enantioselective electrooxidation of sec-alcohols

Article abstract of DOI:10.1016/j.tetlet.2008.06.112

Enantiomerically pure azabicyclo-N-oxyls were prepared from l-hydroxyproline. They mediated enantioselective electrooxidation of racemic sec-alcohols to afford optically active sec-alcohols with moderate to high s value (up to 21).

Full text of DOI:10.1016/j.tetlet.2008.06.112

Tetrahedron Letters 49 (2008) 5247–5251
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chiral azabicyclo-N-oxyls mediated enantioselective electrooxidation
of sec-alcohols
*
Hirofumi Shiigi, Hiroyuki Mori, Tomoaki Tanaka, 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:
Enantiomerically pure azabicyclo-N-oxyls were prepared from L-hydroxyproline. They mediated enantio-
Received 21 April 2008
Revised 20 June 2008
Accepted 26 June 2008
Available online 1 July 2008
selective electrooxidation of racemic sec-alcohols to afford optically active sec-alcohols with moderate to
high s value (up to 21).
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Chiral nitroxyl radical
Enantioselective oxidation
Optically active alcohol
Electrooxidation
2,2,6,6-Tetramethylpiperidine-N-oxyl (TEMPO) has been uti-
lized in chemical1 and electrochemical oxidation2 of alcohols as a
mediator. Also, optically active N-oxyls structurally modified from
TEMPO were effective for oxidative kinetic resolution of sec-alco-
hols by chemical and electrochemical methods.3 We have recently
reported preparation of several azabicyclo-N-oxyls and their medi-
atory role for electrooxidation of alcohols.4 This oxidation was
applicable to a transformation of sterically hindered secondary
alcohols into the corresponding ketones in higher yields than those
of TEMPO-mediated reactions (Eq. 1). We wish to report herein the
preparation of enantiomerically pure azabicyclo-N-oxyls and their
mediatory role for enantioselective electrooxidation of racemic
sec-alcohols.5
The chiral azabicyclo skeleton was prepared from
proline as shown in Eq. 2. Namely, the electrooxidation of N-
methoxycarbonyl- -hydroxyproline ethyl ester (1) afforded meth-
L-hydroxy-
L
oxylated compound 2 in 94% yield, which was allylated with allyl-
trimethylsilane catalyzed by TiCl4 to give allylated compound 3 as
a diastereomer mixture. Alkaline hydrolysis of 3 followed by elec-
trooxidation afforded methoxylated diastereomeric mixture 4 in
70% yield. TiCl4-catalyzed cyclization6 for (2S)-isomer of 4 afforded
the corresponding azabicyclo compound 5 in enantiomerically
O
N
-[e], 3.0 F/mol, NaBr (4.0 equiv)
A or TEMPO (0.1 equiv)
ð1Þ
CH2Cl2/sat. aq. NaHCO3, rt
N
O
OH
O
Cl
A: 99%
TEMPO: 23%
* Corresponding author. Tel.: +81 95 819 2429; fax: +81 95 819 2476.
E-mail address: onomura@nagasaki-u.ac.jp (O. Onomura).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.112

5248
H. Shiigi et al. / Tetrahedron Letters 49 (2008) 5247–5251
HO
MeO
HO
HO
1) SOCl2, EtOH,
-2e, 4 F/mol
80 °C, 12 h
CO2Et
CO2H
CO2Et
N
N
H
N
MeCN/MeOH,
0 °C
2) ClCO2Me, Et3N,
DMAP, CH2Cl2,
50 °C, 12 h
CO2Me
CO2Me
2
94%
L-Hydroxyproline
1
90% for 2 steps
HO
S
HO
TiCl4,
1) NaOH/MeOH,
rt, 12 h
allylSiMe3
R
N
CO2Me
COOEt
COOEt
N
+
CH2Cl2,
-78 °C to rt,
12 h
2) -2e, 3 F/mol
NaOMe/MeOH,
0 °C
ð2Þ
CO2Me
3 (a mixture of diastereomers)
60% (5
HO
S
: 5
R
= 65 : 35)
CO2Me
N
HO
S
TiCl4
HO
N
RN
CO2Me
+
polar components
OMe
OMe
+
CH2Cl2,
-78 °C to rt,
12 h
Cl
CO2Me
4 (a mixture of diastereomers)
5
70% for 2 steps
52 %
pure form,7 while (2R)-isomer of 4 did not give the corresponding
cyclized product but gave polar components.
catalytic amount of 7a–m, excess amount of sodium bromide,
and a mixture of CH2Cl2 and saturated aqueous NaHCO3 as solvent.
After passing through 1.5 F/mol of electricity at constant current
(20 mA, terminal voltage: ca. 3 V) at 0 °C, acetophenone 9 and
(S)-8 were obtained. The results are shown in Table 2. 0.1 equiv
of N-oxyl 7a did not work as a mediator for oxidation at all (entry
1).13 In the case of using acetylated N-oxyl 7b, pivaloylated 7c,
3,5-dimethylbenzoylated 7e, and 2-phenylbenzoylated 7f, (S)-8
Enantiomerically pure azabicyclo-N-oxyls 7a and 7b–k attached
with various O-protecting groups were synthesized by usual meth-
ods as shown in Eq. 3. The yields are summarized in Table 1. Acyl-
ation for hydroxyl group of 5 gave 6b–k.8 After N-methoxycarbonyl
group of 5 and 6b–k were removed with Me3SiI, successive oxida-
tion with mCPBA afforded N-oxyls 7a–k.9
CO2Me
N
O
N
DIPEA, DMAP
Acyl chloride
O
O
1) TMS-I, CH2Cl2, rt, 12 h
PG
PG
ð3Þ
5
CH2Cl2, 50 °C, 12 h
2) mCPBA, CH2Cl2, rt, 3 h
Cl
Cl
6b-k
7a-k
Cyclic voltammogram for 7g showed reversible wave pattern
similar to that for azabicyclo-N-oxyl A.4,10 This strongly suggests
that enantiomerically pure azabicyclo-N-oxyls could also play the
role of an oxidation mediator just like A (Fig. 1).
was recovered with low s value (entries 2, 3, 5, and 6),14 while
use of benzoylated 7d afforded (S)-8 with moderate s value of 8
(entry 4). The most efficient N-oxyl 7g which was protected with
The enantioselective electrooxidation of DL-1-phenylethanol (8)
catalyzed with chiral azabicyclo-N-oxyls 7a–m was carried out as
follows (Eq. 4).11 That is, the oxidation was conducted using plati-
num electrodes in an undivided beaker-type cell, containing a
40
30
20
10
0
Table 1
Preparation of enantiomerically pure N-oxyls 7a–k
Entry
PG
Yield of 6b–k (%)
Yield of 7a–k (%)
1
2
3
4
5
6
7
8
9
H
Acetyl
Pivaloyl
Benzoyl
3,5-Dimethylbenzoyl
2-Phenylbenzoyl
1-Naphthoyl
1-(2-Methylnaphthoyl)
2-Naphthoyl
Tosyl
—
7a
7b
7c
7d
7e
7f
7g
7h
7i
35
65
50
59
47
30
57
37
70
48
57
6b
6c
6d
6e
6f
6g
6h
6i
88
49
96
54
70
67
31
75
73
66
-10
-20
-30
-0.1
+0.4
+0.9
+1.4
Potential, V
10
11
6j
6k
7j
7k
Phenylcarbamoyl
Figure 1. Cyclic voltammogram for 7g.

H. Shiigi et al. / Tetrahedron Letters 49 (2008) 5247–5251
5249
Table 2
chiral mediator for the enantioselective oxidation, 0.05 equiv of
7g was somewhat ineffective for enantioselectivity (entries 8–10).
Enantioselective oxidation of DL-phenylethanol (8) catalyzed by 7a–m
Entry
N-oxyl
Yield of
Yield of recovered
% ee of
s
7a–m (equiv)
9 (%)
(S)-8 (%)
(S)-8
7a-m (0.05-0.5 equiv)
NaBr (4.0 equiv)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
7a (0.1)
7b (0.1)
7c (0.1)
7d (0.1)
7e (0.1)
7f (0.1)
7g (0.1)
7g (0.05)
7g (0.2)
7g (0.5)
7h (0.1)
7i (0.1)
7j (0.1)
7k (0.1)
7l (0.1)
7m (0.1)
14
58
44
38
60
42
43
45
42
42
51
42
35
50
43
41
86
33
56
57
33
57
56
50
54
53
49
57
44
44
43
59
0
7
0
1
2
8
2
5
21
10
20
20
3
Pt(+)−Pt(-), 1.5 F/mol, 20 mA
OH
O
OH
19
47
23
38
64
62
64
65
37
41
13
27
42
22
+
sat. aq.NaHCO3/CH2Cl2, 0 °C
Ph
Ph
Ph
Recovered
)-8
0.5 mmol
(
S
8
9
ð4Þ
Table 3 summarizes the enantioselective oxidation of some sec-
alcohols 10–14 mediated by 7g, which was passed through 1.5 F/
mol of electricity at constant current (20 mA, terminal voltage:
ca. 3 V) at 0 °C (Eq. 5). (S)-1-(2-Methylphenyl)ethanol ((S)-10)
and (S)-1-(2,4,6-trimethylphenyl)ethanol ((S)-11) were obtained
in 47% yield with 72% ee for (S)-10 (entry 1) and in 47% yield with
64% ee for (S)-11 (entry 2). Although in the case of 1-(1-naphthale-
nyl)ethanol (12) and 1-indanol (14), (S)-12 and (S)-14 were
obtained with low s values of 6 and 5, respectively (entries 3 and
5), 1-(2-naphthalenyl)ethanol (13) gave (S)-13 with good s value
of 11 (entry 4).
5
2
2
4
2
O
N
X = Br : 7l
H : 7m
O
O
X
Scheme 1 shows our proposed mechanism for kinetic resolution
of DL-8 mediated by chiral N-oxyl 7g. The carbonyl group of
N-oxoammonium ion 7g0, which is generated by the oxidation of
7g with bromonium ion, might coordinate to the oxoammonium
group. Since (R)-8 can smoothly approach 7g0 to form the
active intermediate, (R)-8 might be easily oxidized to afford
1-naphthoyl group gave (S)-8 with high s value of 21 (entry 7).
Other N-oxyls 7h–m were less effective than 7g (entries 11–
16).15,16 Although 0.2 or 0.5 equiv of N-oxyl 7g worked well as a
7g (0.1 equiv)
NaBr (4.0 equiv)
sec-Alcohol
Recovered
(S)-alcohol
Ketone
+
ð5Þ
Pt(+)−Pt(-), 1.5 F/mol, 20 mA
sat. aq.NaHCO3/CH2Cl2, 0 °C
10-14
15-19
(S)-10-14
Table 3
Enantioselective oxidation of various sec-alcohols 10–14 catalyzed by 7g
Entry
sec-Alcohol
Yield of ketone (%)
Yield of recovered (S)-alcohol (%)
% ee of (S)-10–14
s
Me OH
1
10
11
15
43
49
47
72
18
Me OH
2
16
47
64
8
Me
Me
OH
3
4
5
12
13
14
17
18
19
40
52
52
60
45
47
39
76
53
6
11
5
OH
OH

5250
H. Shiigi et al. / Tetrahedron Letters 49 (2008) 5247–5251
-e
O
1/2Br+
1/2Br-
O
N
N
O
C
O
C
O
O
Cl
7g
7g'
Cl
Me
Me
H
H
R
S
(
R)-8
HO
(S
)-8
HO
-H+
7g'
-H+
7g'
Me
Me
H
H
O-
O
O-
C
O
O
C
N
O
N
O
O
Cl
Cl
Me
Me
O
O
9
9
Scheme 1. Plausible stereochemical course for kinetic resolution of DL-8.
to 2.5): Graetz, B.; Rychnovsky, S.; Leu, W.; Farmer, P.; Lin, R. Tetrahedron:
Asymmetry 2005, 16, 3584–3598.
acetophenone (9). On the other hand, the formation of intermedi-
ate composed of (S)-8 and 7g0 seems to be somewhat difficult.
In summary, we report preparation of enantiomerically pure
azabicyclo-N-oxyls and their mediatory role for enantioselective
electrooxidation of racemic sec-alcohols. O-Protecting group on
azabicyclo-N-oxyls affected the enantioselectivity for the oxidation
of sec-alcohols. Further modification of chiral N-oxyls is underway.
6. Physical data for 5: Colorless oil. ½a D24
ꢀ
+5.6 (c 1.0, CHCl3). IR (neat): 3480, 2955,
1705 cmꢁ1 1H NMR (300 MHz, CDCl3) d 4.42 (br s, 1H), 4.25 (d, J = 6.4 Hz, 1H),
.
4.11 (br s, 1H), 4.11–3.98 (m, 1H), 3.74 (s, 3H), 2.80–2.50 (br s, 1H), 2.21–1.80
(m, 6H). [HR-FAB(+)]: m/z calcd for C9H15ClNO3 [M+H]+ 220.0740: found
220.0735.
7. The optical purity of 5 was determined after conversion to 1-naphthoylated N-
oxyl 7g by chiral HPLC: Daicel Chiralcel OD-H column (4.6 mm£, 250 mm), n-
hexane/isopropanol = 5:1, wavelength: 254 nm, flow rate: 1.0 mL/min,
retention time: 12.3 min for (6R)-7g, 17.4 min for (6S)-7g.
Acknowledgments
8. The stereoconfiguration for 6g was deduced by NOE correlation.
This work was supported in part by a Grant-in-Aid for Young
Scientists (B) (19790017) from the Ministry of Education, Science,
Sports and Culture, Japan, a Grant-in-Aid for Scientific Research (C)
(19550109) from Japan Society for the Promotion of Science, and a
Konica Minolta Imaging Science Foundation, Japan.
CO2Me
N
O
6g
O
H
Cl
H
References and notes
H
NOE
1. Representative recent reviews: (a) de Nooy, A. E. J.; Besemer, A. C.; van
Bekkum, H. Synthesis 1996, 1153–1174; (b) Sheldon, A. R.; Arends, W. C. E. I.
Adv. Synth. Catal. 2004, 346, 1051–1076.
2. (a) Semmelhack, M. F.; Chou, C. S.; Cortes, D. A. J. Am. Chem. Soc. 1983, 105,
4492–4494; (b) Osa, T.; Akiba, U.; Segawa, I.; Bobbitt, J. M. Chem. Lett. 1988, 8,
1423–1426; (c) Inokuchi, T.; Matsumoto, S.; Torii, S. J. Org. Chem. 1991, 56,
2416–2421; (d) Yoshida, T.; Kuroboshi, M.; Oshitani, J.; Gotoh, K.; Tanaka, H.
Synlett 2007, 2691–2694.
3. (a) Ma, Z.; Huang, Q.; Bobbit, J. M. J. Org. Chem. 1993, 58, 4837–4843; (b)
Rychnovsky, S. D.; McLernon, T. L.; Rajapakse, H. J. Org. Chem. 1996, 61, 1194–
1195; (c) Kashiwagi, Y.; Kurashima, F.; Kikuchi, C.; Anzai, J.; Osa, T.; Bobbit, J. M.
Tetrahedron Lett. 1999, 40, 6469–6472; (d) Kuroboshi, M.; Yoshihisa, H.;
Cortona, M. N.; Kawakami, Y.; Gao, Z.; Tanaka, H. Tetrahedron Lett. 2000, 41,
8131–8135.
9. Physical data for 7g: Red amorphous. ½a D27
ꢁ13.3 (c 1.0, CHCl3). IR (neat): 2930,
ꢀ
1717 cmꢁ1. [HR-EI]: m/z calcd for C18H17ClNO3 [M]+ 330.0897; found 330.0899.
10. Cyclic voltammogram for 7g was measured in 0.1 M Et4NBF4/MeCN solution
using glassy-carbon as a working electrode, platinum as a counter electrode,
and Ag/0.01 M AgNO3 as a reference electrode. Concentration of 7g: 1.0 mM.
Scan rate: 30 mV/s. Cyclic voltammogram for other O-acyloxylated N-oxyls
7b–f,h–m showed reversible wave pattern similar to that for 7g, while that for
hydroxylated N-oxyls 7a was irreversible.
11. Representative procedure for the enantioselective electrooxidation of sec-
alcohols: Anodic oxidation of -1-phenylethanol (DL-8) was carried out using
platinum electrodes (1 cm ꢂD2Lcm) in an undivided beaker-type cell. DL-8
(61 mg, 0.5 mmol), 7g (16.5 mg, 0.05 mmol), and NaBr (206 mg, 2.0 mmol)
were added into a mixture of CH2Cl2 (2.5 mL) and saturated aqueous NaHCO3
(2.5 mL). After passing through 1.5 F/mol of electricity at constant current
(20 mA) at 0 °C, the mixture was poured in water and extracted with AcOEt
(20 mL ꢂ 3). The combined organic layer was dried over MgSO4 and the solvent
removed under reduced pressure. The residue was purified by silica gel column
4. Demizu, Y.; Shiigi, H.; Oda, T.; Matsumura, Y.; Onomura, O. Tetrahedron Lett.
2008, 49, 48–52.
5. We found only one literature for enantioselective chemical oxidation mediated
by C2 symmetrical azabicyclo-N-oxyls with low enantioselectivities (s value: up

H. Shiigi et al. / Tetrahedron Letters 49 (2008) 5247–5251
13. DL-8 was oxidized in the absence of N-oxyl to afford 9 with 16% yield.
5251
chromatography (n-hexane/AcOEt = 10:1) to afford acetophenone 9 (25.8 mg,
43% yield) and (S)-8 (34.2 mg, 56% yield) as a colorless oil.12
12. The optical purity of (S)-8 was determined by chiral HPLC: Daicel Chiralcel OB
column (4.6 mm£, 250 mm), n-hexane/isopropanol = 15:1, wavelength:
254 nm, flow rate 0.5 mL/min, retention time: 13.5 min for (S)-8, 17.5 min
for (R)-8.
14. Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; Eliel, E. L., Ed.; Wiley &
Sons: New York, 1988; Vol. 18, pp 249–330.
15.
A
precursor for N-oxyl 7l was synthesized by TiBr4-catalyzed cyclization
of 4.
16. A precursor for N-oxyl 7m was synthesized by reductive dechlorination of 5.