Convenient synthesis of an enantiomerically pure bicyclic proline and its N-oxyl derivatives

Article abstract of DOI:10.1016/j.tetasy.2008.12.011

An enantiomerically pure bicyclic proline derivative was prepared by cis-selective allylation and diastereospecific intramolecular alkylation starting from d-pipecolinic acid. In addition, enantiomerically pure azabicyclo N-oxyls derived from the bicyclic proline worked well as catalysts for the enantioselective electrooxidation of racemic sec-alcohols to afford optically active sec-alcohols in moderate enantiomeric purity.

Full text of DOI:10.1016/j.tetasy.2008.12.011

Tetrahedron: Asymmetry 19 (2008) 2659–2665
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Convenient synthesis of an enantiomerically pure bicyclic proline
and its N-oxyl derivatives
*
Yosuke Demizu, Hirofumi Shiigi, Hiroyuki Mori, Kazuya Matsumoto, 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:
An enantiomerically pure bicyclic proline derivative was prepared by cis-selective allylation and diaste-
reospecific intramolecular alkylation starting from D-pipecolinic acid. In addition, enantiomerically pure
azabicyclo N-oxyls derived from the bicyclic proline worked well as catalysts for the enantioselective
electrooxidation of racemic sec-alcohols to afford optically active sec-alcohols in moderate enantiomeric
Received 12 September 2008
Accepted 3 December 2008
Available online 10 January 2009
purity.
Ó 2008 Elsevier Ltd. All rights reserved.
H
1. Introduction
5
2
N
COOH
HO2C
N
H
N
H
COOH
Recently, the importance of quaternary a-amino acids and their
peptides has continued to increase in the fields of medicinal chem-
istry and protein engineering.1 Since quaternary
a
-amino acids are
A
D-pipecolinic acid
A1
non-proteinogenic, their synthesis has attracted considerable
attention.2 Among them, bicyclic proline analogues A bridged at
the 2nd and 5th carbons of the pyrrolidine ring have unique biolog-
ical3 and conformational4 properties. Therefore, several synthetic
methods for their preparation have been developed (Fig. 1).5
However, to the best of our knowledge, the synthesis of enantio-
merically enriched bicyclic proline A1 with an 8-azabicy-
clo[3.2.1]octane skeleton has not been accomplished to date.6
Herein, we report a convenient method for the synthesis of A17
Figure 1. Structure of bicyclic proline analogue A.
allylated pipecolinate cis-3.10 After isolation of cis-3 by chromatog-
raphy, transformation of the 6-allyl group into a tosyloxyethyl
group was carried out by ozonolysis and then by NaBH4 reduction
followed by tosylation to obtain 5 in sufficiently high yield. Finally,
compound 5 underwent a base-catalyzed intramolecular alkyl-
ation5d,11 to afford enantiomerically pure 6 with an 8-azabicy-
clo[3.2.1]octane skeleton in high yield. Further alkaline
hydrolysis of 6 gave N-protected bicyclic proline 7 in quantitative
yield.
starting from D-pipecolinic acid. In addition, chiral N-oxyls derived
from A1 were prepared and used for the enantioselective electro-
oxidation of DL-1-phenylethanol.8
The stereochemistry of 6 was determined by X-ray crystallo-
graphic analysis after derivatization of 7 to heterotripeptide 8.12
2. Results and discussion
The transformation was carried out via
a solution-phase
method, employing 1-ethyl-3-(3-dimethylaminopropyl)carbodi-
imide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt) as
coupling reagents (Eq. 1). As shown in Figure 2, the bicyclic proline
analogue has conformational properties similar to those of proline,
which is a b-turn inducer.13
2.1. Synthesis of bicyclic proline derivative 6
Our strategy for synthesis of bicyclic proline derivative 6 is
shown in Scheme 1, which consists of cis-selective allylation and
diastereospecific intramolecular alkylation. To start with, electro-
chemical methoxylation9 of
D-pipecolinic acid derivative 1 afforded
EDC (1.2 equiv)
CO2Me
O
HOBt (1.2 equiv)
6-methoxypipecolinate 2, which was allylated with allyltrimethyl-
silane catalyzed by BF3–OEt2 to give diastereomerically enriched 6-
H
N
H2N-(Aib)2-OMe (1.0 equiv)
MeO2C
N
N
H
7
MeCN, 60°C
O
8
, 78%
ð1Þ
* Corresponding author. Tel.: +81 95 819 2429; fax: +81 95 819 2476.
E-mail address: onomura@nagasaki-u.ac.jp (O. Onomura).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.011

2660
Y. Demizu et al. / Tetrahedron: Asymmetry 19 (2008) 2659–2665
2.2. Synthesis of enantiomerically pure N-oxyls 10, 13,
and 16a–d
electricity at constant current (20 mA, terminal voltage: ca.
3 V) at 0 °C, acetophenone 18 and (S)-17 were obtained. The re-
sults are shown in Table 2. The use of N-oxyls 10 and 16a–d
afforded (S)-17 with moderate S values16 (entries 1, 3, and 4–
6), while (S)-17 was recovered with low enantioselectivity when
N-oxyl 13 was used (entry 2).
The enantioselective oxidations of other sec-alcohols 19–24
mediated by 16b were examined (Eq. 6). Table 3 summarizes the
results. In all cases, (S)-alcohols 19–24 were recovered with low
to moderate S values.
Scheme 2 shows our proposed mechanism for the kinetic res-
olution of DL-17 mediated by chiral N-oxyl 16b. Compound DL-17
has prospects to approach 16b0 generated by the oxidation of 16b
with a bromonium ion from path a or path b. In the case of path
a, since (R)-17 can smoothly approach 16b0 to form the active
intermediate, (R)-17 can be easily oxidized to afford acetophe-
none 18. On the other hand, the formation of intermediate com-
posed of (S)-17 and 16b seems to be somewhat difficult. Also, in
the case of path b, the intermediate seems to be somewhat unsta-
ble because the distance O–HaꢀꢀꢀOa@C is too long for a hydrogen
bond.
Enantiomerically pure azabicyclo-N-oxyl 10 possessing
a
methoxycarbonyl group at the bridgehead position was synthe-
sized from 6 by deprotection of the N-methoxycarbonyl group uti-
lizing Me3SiI, followed by m-CPBA oxidation (Eq. 2). N-Oxyl 13 was
synthesized as follows: reduction of the methyl ester group fol-
lowed by benzoylation of the hydroxyl group gave compound 11
in moderate yield. After deprotection of 11, successive oxidation
with mCPBA afforded N-oxyl 13 (Eq. 3).
O
N
H
N
MeO2C
MeO2C
Me3SiI (3.0 equiv)
CH2Cl2, rt
m-CPBA (1.5 equiv)
6
6
ð2Þ
CH2Cl2, rt
9, 73%
10, 79%
CO2Me
N
H
N
1) DIBAL-H (3.0 equiv)
toluene, 0°C to rt
BzO
BzO
Me3SiI (3.0 equiv)
CH2Cl2, rt
2) BzCl, Et3N
CH2Cl2, rt
11, 56%
12, 99%
3. Conclusion
ð3Þ
O
N
We have accomplished a convenient method for synthesis of
enantiomerically pure bicyclic proline analogues starting from
m-CPBA (1.5 equiv)
BzO
CH2Cl2, rt
D-pipecolinic acid. It has conformational properties similar to
those of proline, which is a b-turn inducer. Chiral azabicyclo
N-oxyls derived from bicyclic amino acid worked well as cata-
lysts in the enantioselective electrooxidation of racemic sec-
alcohols to afford optically active sec-alcohols with moderate S
values.
13, 48%
Compounds 14a–d, which were substituted with several amide
groups, were prepared by using a solution-phase method (Eq. 4).
N-Oxyls 16a–d were prepared via a method similar to that de-
scribed for the preparation of N-oxyl 10. The results are summa-
rized in Table 1.
4. Experimental
4.1. General
CO2Me
N
Electrochemical reactions were carried out using DC Power Sup-
ply (GP 050–2) of Takasago Seisakusho, Inc. 1H NMR spectra were
measured on a Varian Gemini 300 and 400 spectrometer with TMS
as an internal standard. 13C NMR spectra were measured on a Var-
ian Gemini 300 and 400 spectrometer with TMS as an internal
standard. IR spectra were obtained on a Shimadzu FTIR-8100A.
Mass spectra were obtained on a JEOL JMS-DX 303 instrument.
All reagents and solvents were used as supplied without further
purification.
O
O
EDC (1.2 equiv)
HOBt (1.2 equiv)
H
N
R
R
Me3SiI (3.0 equiv)
CH2Cl2, rt
N
H
N
H
7
RNH2 (1.2 equiv)
MeCN, 60°C
14a d
15a d
-
-
ð4Þ
O
N
O
m-CPBA (1.5 equiv)
R
N
CH2Cl2, rt
H
Although we could not determine the enantiomeric purities for
compounds 7, 9, 10, 11, 12, 13, 14a–d, 15a–d, and 16a–d, it was as-
sumed that there was no racemization during their derivation from
enantiomerically pure 6.
16a d
-
The cyclic voltammogram for 10 showed a reversible wave pat-
tern similar to that of TEMPO.14 This fact strongly suggests that
enantiomerically pure azabicyclo-N-oxyls could also play the role
of an oxidation mediator such as TEMPO (Fig. 3).
10, 13, 16a-d (0.1 equiv)
OH
O
OH
NaBr (4.0 equiv)
+
Ph
Ph
Ph
ð5Þ
Pt electrodes, 1.5 F/mol,
2.3. Enantioselective electrooxidation of DL-1-phenylethanol
mediated by chiral azabicyclo-N-oxyls 10, 13, and 16a–d
20 mA, 3V
Recovered
17
(S)-
sat. aq.NaHCO3/CH2Cl2, 0°C
17
18
The enantioselective electrooxidation of DL-1-phenylethanol
178a,15 mediated by chiral azabicyclo-N-oxyls 10, 13, and 16a–
d was carried out in an undivided beaker-type cell having plat-
inum electrodes as follows (Eq. 5): that is, oxidation was con-
ducted, using a catalytic amount of N-oxyl, an excess amount
of sodium bromide, and a mixture of CH2Cl2 and saturated
aqueous NaHCO3 as solvent. After passing through 1.5 F/mol of
4.2. Procedure for the synthesis of enantiomerically pure
proline analogue
Methyl N-methoxycarbonyl-
N-methoxycarbonyl-6-methoxy-
L
-pipecolinate ent-110 and methyl
L
-pipecolinate ent-210 are known
compounds.

Y. Demizu et al. / Tetrahedron: Asymmetry 19 (2008) 2659–2665
2661
8H); 13C NMR (100 MHz, CDCl3) d = 172.8, 157.9, 58.7, 53.3, 52.4,
52.1, 46.8, 35.6, 29.4, 26.0, 16.0; [HR-FAB(+)]: m/z calcd for
C11H20NO5 [M+H]+ 246.1342: found 246.1345.
16b (0.1 equiv)
OH
R2
19 24
O
OH
R2
(S)-19-24
NaBr (4.0 equiv)
+
R1
R1
R2
R1
4.2.3. Methyl N-methoxycarbonyl-(6S)-[2-(p-tolunesulfonyloxy)-
ð6Þ
Pt(+)−Pt(-), 1.5 F/mol,
20 mA, 3V
ethyl]-D-pipecolinate 5
25 30
-
-
sat. aq.NaHCO3/CH2Cl2, 0°C
At first, p-TsCl (120 mg, 0.63 mmol), Et3N (88
lL, 0.63 mmol),
and 4-DMAP (13.4 mg, 0.11 mmol) were added into 4 (130 mg,
0.53 mmol) in CH2Cl2 (3.0 mL) and the mixture was stirred for
24 h at room temperature. Upon completion of the reaction, the
mixture was poured into 3% aqueous HCl and was extracted with
CHCl3 (10 mL ꢂ 3). The combined organic layer was dried over
anhydrous MgSO4 and the solvent was removed under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (n-hexane:AcOEt = 4:1) to afford 5 as a colorless oil (205 mg,
4.2.1. Methyl N-methoxycarbonyl-(6S)-allyl-D-pipecolinate cis-3
Under a nitrogen atmosphere, BF3–OEt2 (4.2 mL, 34.2 mmol)
was added dropwise to 2 (7.5 g, 32.6 mmol) and allyltrimethylsi-
lane (9.8 mL, 61.9 mmol) in CH2Cl2 (200 mL) at ꢁ78 °C, then the
mixture was stirred for 3 h and allowed to stand until it warmed
to ꢁ40 °C. The resulting mixture was poured into ice water and
was extracted with CHCl3 (300 mL ꢂ 3). The combined organic
layer was dried over anhydrous MgSO4 and the solvent was re-
moved under reduced pressure. The residue was purified by silica
gel column chromatography (n-hexane:AcOEt = 5:1; cis-3 was less
polar than trans-3) to afford cis-3 as a colorless oil (5.7 g, 72%).
97%).
½
a 2D0
ꢃ
¼ þ61:5 (c 1.0, CHCl3); IR (neat)
m = 2953, 1742,
1701 cmꢁ1
;
1H NMR (300 MHz, CDCl3) d = 7.80 (d, J = 8.4 Hz, 2H),
7.35 (d, J = 8.1 Hz, 2H), 4.89 (br s, 1H), 4.36–4.33 (m, 1H), 4.14–
4.12 (m, 2H), 3.69 (s, 3H), 3.68 (s, 3H), 2.45 (s, 3H), 2.29 (d,
J = 14.4 Hz, 1H), 2.08–1.98 (m, 1H), 1.77–1.40 (m, 6H); 13C NMR
(100 MHz, CDCl3) d = 173.0, 156.8, 144.6, 133.0, 129.8, 128.0,
68.4, 53.0, 52.3, 47.6, 32.0, 28.5, 25.9, 21.6, 15.7; [HR-FAB(+)]: m/
z calcd for C18H26NO7S [M+H]+ 400.1430: found 400.1449.
½
a 2D0
ꢃ
¼ þ106:6 (c 1.0, CHCl3); IR (neat)
m = 2951, 1752, 1713,
1642 cmꢁ1 1H NMR (300 MHz, CDCl3) d = 5.80–5.63 (m, 1H),
;
5.07–5.01 (m, 2H), 4.86 (br s, 1H), 4.21 (br s, 1H), 3.74 (s, 3H),
3.71 (s, 3H), 2.42–2.10 (m, 3H), 1.78–1.47 (m, 5H); 13C NMR
(100 MHz, CDCl3) d = 156.8, 136.0, 116.8, 52.8, 52.3, 52.1, 50.8,
36.3, 26.0, 25.8, 15.3; [HR-FAB(+)]: m/z calcd for C12H20NO4
[M+H]+ 242.1393: found 242.1404.
4.2.4. Methyl (1R)-N-methoxycarbonyl-8-azabicyclo[3.2.1]
octane-1-carboxylate 6
Under
a nitrogen atmosphere, 1.9 M NaHMDS (2.5 mL,
4.7 mmol) in n-hexane was added dropwise to 5 (1.56 g, 3.9 mmol)
in THF (40 mL) at ꢁ78 °C, then the mixture was stirred at ꢁ78 °C
for 12 h and allowed to stand until it warmed to room tempera-
ture. The mixture was then poured into saturated aqueous NH4Cl
and was extracted with AcOEt (40 mL ꢂ 3). The combined organic
layer was dried over anhydrous MgSO4 and the solvent was re-
moved under reduced pressure. The residue was purified by silica
gel column chromatography (n-hexane:AcOEt = 5:1) to afford 6 as
4.2.2. Methyl N-methoxycarbonyl-(6S)-(2-hydroxyethyl)-
nate 4
D-pipecoli-
Ozone gas was bubbled into a solution of 3 (241 mg, 1.0 mmol)
in CH2Cl2 (5.0 mL) at ꢁ78 °C, and the reaction was monitored by
TLC. After the disappearance of 3, NaBH4 (304 mg, 8.0 mmol) dis-
solved in MeOH (1.0 mL) was added dropwise to the mixture and
was stirred at 50 °C for 6 h. The mixture was poured into 3% aque-
ous HCl and was extracted with CHCl3 (20 mL ꢂ 3). The combined
organic layer was dried over anhydrous MgSO4 and the solvent was
removed under reduced pressure. The residue was purified by sil-
ica gel column chromatography (n-hexane:AcOEt = 1:1) to afford 4
a colorless oil (761 mg, 86%). ½a D23
ꢃ
¼ þ25:0 (c 1.0, CHCl3, >99% ee);
IR (neat)
m ;
= 2953, 1750, 1709 cmꢁ1 1H NMR (300 MHz, CDCl3)
d = 4.33 (br s, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 2.25–1.39 (m, 10H);
13C NMR (100 MHz, CDCl3) d = 172.8, 154.9, 65.2, 56.9, 52.4, 52.2,
34.1, 29.8, 29.6, 27.3, 17.0; [HR-FAB(+)]: m/z calcd for C11H18NO4
[M+H]+ 228.1236: found 228.1237. HPLC: Daicel Chiralcel OJ-H col-
umn, n-hexane:ethanol = 20:1, wavelength: 210 nm, flow rate:
1.0 mL/min, retention time: 8.2 min for (S)-6, 11.1 min for (R)-6.
as a colorless oil (198 mg, 81%). ½a D20
ꢃ
¼ þ50:2 (c 1.0, CHCl3); IR
(neat)
m ;
= 3500 (br), 2953, 1736, 1700 cmꢁ1 1H NMR (300 MHz,
CDCl3) d = 4.84 (br s, 1H), 4.50 (br s, 1H), 3.75 (s, 3H), 3.70 (s,
3H), 3.69–3.63 (m, 2H), 2.30 (d, J = 12.0 Hz, 1H), 1.81–1.43 (m,
allyl-SiMe3 (1.9 equiv)
BF3-Et2O (1.05 equiv)
-[e] (3 F/mol)
MeO
N
CO2Me
N
CO2Me
N
CO2Me
Et4NBF4
CH2Cl2
CO2Me
CO2Me
CO2Me
-78 °C to -40 °C
MeCN/MeOH
cis- and trans-3
(major diastereomer: cis)
2, 98%
1, 99%
p-TsCl (1.2 equiv)
Silica gel column
chromatography
1) O3, CH2Cl2
-78°C
Et3N (1.2 equiv)
cis-3
HO
N
CO2Me
DMAP (0.2 equiv)
CH2Cl2, rt
2) NaBH4 (8.0 equiv)
MeOH, 50 °C
CO2Me
, 81%
4
2
72% from
CO2Me
N
CO2Me
N
MeO2C
HO2C
NaHMDS (1.2 equiv)
THF, -78 °C to rt
1M NaOH aq.
MeOH, 60°C
TsO
N
CO2Me
CO2Me
6
7, quant.
, 86%, >99% ee
5, 97%
Scheme 1.

2662
Y. Demizu et al. / Tetrahedron: Asymmetry 19 (2008) 2659–2665
Table 2
Enantioselective oxidation of DL-phenylethanol (17) mediated by 10, 13, and 16a–d
Entry
N-oxyl
Yield of
Yield of recovered
% ee of
S
18 (%)
(S)-17 (%)
(S)-17
1
2
3
4
5
6
10
13
16a
16b
16c
16d
59
50
64
50
45
53
41
41
36
50
51
36
49
7
53
59
42
69
3
1
3
7
4
6
H-bond
Table 3
Enantioselective oxidation of various sec-alcohols 19–24 mediated by 16b
Entry
sec-Alcohol
Yield of
Yield of recovered % ee of
S
ketone (%)
(S)-alcohol
(S)-19–24
Figure 2. Ortep drawing of tripeptide 8.
Me OH
1
2
19
25
26
50
54
48
33
16
3
Table 1
Preparation of enantiomerically pure N-oxyls 16a–d
Me OH
Entry
RNH2
Yield of 14a–d (%)
15a–d (%)
16a–d (%)
20
45
2
1
2
3
4
Ph–NH2
Bn–NH2
Methyl
Methyl
14a (70)
14b (78)
14c (78)
14d (83)
15a (51)
15b (74)
15c (86)
15d (83)
16a (85)
16b (82)
16c (86)
16d (68)
L
-Phga
-Phb
Me
Me
OH
D
Ph
a
3
4
21
22
27
28
62
70
35
29
30
69
2
3
H2N
CO2Me
Ph
b
H2N
CO2Me
OH
80
OH
5
5
23
24
29
30
53
66
46
24
38
72
3
4
60
40
20
OH
0
-20
ring of solution was continued at 60 °C for 48 h. The solution was
then neutralized with 3% aqueous HCl, and then MeOH was evap-
orated. The residue was diluted with brine, extracted with AcOEt
(20 mL ꢂ 3), and dried over anhydrous MgSO4. Removal of the sol-
vent afforded compound 7 (298 mg, quant.) as a colorless oil,
which was used for the next reaction without further purification.
-40
-60
½
a 2D9
ꢃ
¼ þ21:6 (c 1.0, CHCl3, >99% ee); IR (neat)
m
= 3280 (br), 2955,
-80
1750, 1700 cmꢁ1
;
1H NMR (300 MHz, CDCl3) d = 9.91 (br s, 1H),
0
0.5
1.0
1.5
Potential (V vs Ag/AgNO3)
4.33 (br s, 1H), 3.72 (s, 3H), 2.34–1.40 (m, 10H); 13C NMR
(100 MHz, CDCl3) d = 177.3, 155.3, 65.4, 57.2, 52.6, 34.6, 29.8,
27.3, 20.8, 17.0; [HR-FAB(+)]: m/z calcd for C10H16NO4 [M+H]+
214.1079: found 214.1080.
Figure 3. Cyclic voltammogram for N-oxyl 10.
4.2.5. (1R)-N-Methoxycarbonyl-8-azabicyclo[3.2.1]octane-1-
carboxylic acid 7
4.2.6. Methyl N-[(1R)-N-methoxycarbonyl-8-azabicyclo[3.2.1]
octane-1-carbonyl]dimethylglycyl-dimetylglycinate 8
At first, 1 M aqueous NaOH (5.0 mL) was added to the stirred
solution of 6 (318 mg, 1.4 mmol) in MeOH (5.0 mL), and the stir-
A solution of 7 (213 mg, 1.0 mmol), 1-ethyl-3-(3-dimethylami-
nopropyl)carbodiimide hydrochloride (EDC, 230 mg, 1.2 mmol),

Y. Demizu et al. / Tetrahedron: Asymmetry 19 (2008) 2659–2665
2663
FAB(+)]: m/z calcd for
398.2314.
Crystallographic data: orthorhombic; space group P212121;
C
19H32N3O6 [M+H]+ 398.2291: found
path a
-e
O
N
O
N
alcohol
Bn
O
O
1/2Br+
1/2Br-
Bn
a = 8.7962(5) Å, b = 10.6579(5) Å, c = 22.8155(11) Å;
a, b, c = 90°;
N
H
N
H
V = 2138.93(19) Å3; Z = 4, dcalcd = 1.234 g/cm3; 15,490 reflections
collected 2763 unique (Rint = 0.019); R = 0.0595, wR2 = 0.1330.
16b
16b'
4.3. Preparation of chiral azabicyclo N-oxyls
path a
4.3.1. Methyl (1R)-8-azabicyclo[3.2.1]octane-1-carboxylate 9
Me3SiI (213 lL, 1.5 mmol) was added to stirred solution of 6
Me
Me
H
(114 mg, 0.5 mmol) in CH2Cl2 (2.0 mL), and the solution was stir-
red at rt for 12 h. The solution was then poured into saturated
aqueous NaHCO3 and was extracted with CHCl3 (20 mL ꢂ 3). The
combined organic layer was dried over anhydrous MgSO4 and sol-
vent was removed under reduced pressure to afford 9 as a colorless
oil, which was used for next reaction without further purification.
H
R
S
17
(R)-
HO
17
(S)-
HO
16b'
16b'
½
a 2D8
ꢃ
¼ þ14:3 (c 0.7, CHCl3, >99% ee); IR (neat)
m = 3277 (br), 2953,
1717 cmꢁ1 1H NMR (300 MHz, CDCl3) d = 3.74 (s, 3H), 3.06 (br s,
;
2H), 2.08–1.46 (m, 10H); [HR-EI(+)]: m/z calcd for C9H15NO2 [M]+
Me
H
Me
169.1103: found 169.1108.
H
O
O
H O
H O
4.3.2. Methyl (1R)-8-azabicyclo[3.2.1]octane-1-carboxylate-N-
oxyl 10
O
O
N
N
Bn
Bn
A solution of amine 9 (34 mg, 0.2 mmol) and m-CPBA (52 mg,
0.3 mmol) in CH2Cl2 (1.0 mL) was stirred for 3 h at rt. The solution
was then poured into saturated aqueous NaHCO3 and was ex-
tracted with CHCl3 (10 mL ꢂ 3). The combined organic layer was
dried over anhydrous MgSO4 and solvent was removed under re-
duced pressure. The residue was purified by silica gel column chro-
matography (n-hexane:AcOEt = 3:1) to afford N-oxyl 10 (29 mg,
N
H
N
H
Me
Me
79%) as a red foam. ½a D29
¼ ꢁ13:9 (c 0.6, CHCl3, >99% ee); IR (neat)
ꢃ
m
= 2955, 1748, 1437 cmꢁ1; [HR-FAB(+)]: m/z calcd for C9H14NO3
O
O
18
18
[M+H]+ 184.0974: found 184.0990.
4.3.3. (1R)-N-Methoxycarbonyl-1-benzoyloxymethyl-8-
azabicyclo[3.2.1]octane 11
path b
R'
O
Under an argon atmosphere, 1M DIBAL-H (3.0 mL, 3.0 mmol) in
R
path b
H
O
n-hexane was added dropwise to
a solution of 6 (227 mg,
alcohol
O
N
1.0 mmol) in toluene (5 mL) at 0 °C. The resulting mixture was stir-
red for 12 h and allowed to stand until it warmed to room temper-
ature. The solution was then poured into 3% aqueous HCl and was
extracted with AcOEt (20 mL ꢂ 3). The combined organic layer was
dried over anhydrous MgSO4 and the solvent was removed under
reduced pressure. The residue was purified by silica gel column
chromatography (n-hexane:AcOEt = 3:1) to afford (1R)-N-meth-
oxycarbonyl-1-hydroxymethyl-8-azabicyclo[3.2.1]octane 60 as a
O
N
Bn
Ha
Oa
N
H
Bn
N
H
16b'
R, R' = Me, Ph
colorless oil (183 mg, 86%). ½a D26
¼ ꢁ21:3 (c 0.9, CHCl3, >99% ee);
ꢃ
IR (neat) m
= 3401 (br), 2946, 1673 cmꢁ1; 1H NMR (300 MHz, CDCl3)
Scheme 2. Plausible stereochemical course for the kinetic resolution of DL-17.
d = 5.06 (br s, 1H), 4.30 (br s, 1H), 3.77–3.59 (m, 5H), 2.15–1.25 (m,
10H); 13C NMR (75 MHz, CDCl3) d = 155.2, 66.6, 66.3, 57.6, 52.2,
32.5, 31.9, 30.6, 26.0, 17.4; [HR-EI(+)]: m/z calcd for C10H17NO3
[M]+ 199.1208: found 199.1187.
and 1-hydroxybenzotriazole (HOBt, 162 mg, 1.2 mmol) in MeCN
(5 mL) was stirred at room temperature for 30 min. Then, a solu-
tion of H2N–(Aib)2–OMe (202 mg, 1.0 mmol) in MeCN (5 mL) was
added to the stirred solution and stirring was continued at 60 °C
for 48 h. The solution was evaporated, diluted with AcOEt
(50 mL), washed with 3% aqueous HCl, 5% NaHCO3, and brine,
and dried over anhydrous MgSO4. Evaporation of the solvent gave
a white solid, which was purified by column chromatography on
silica gel (n-hexane:AcOEt = 1:5) to afford 8 (310 mg, 78%) as color-
BzCl (98
l
L, 0.84 mmol) was added to a stirred solution of 60
L, 1.05 mmol) and DMAP (43 mg,
(149 mg, 0.7 mmol), Et3N (147
l
0.35 mmol) in CH2Cl2 (7 mL), and the mixture was stirred at rt
for 12 h. The solution was then poured into 3% aqueous HCl and
was extracted with CHCl3 (20 mL ꢂ 3). The combined organic layer
was dried over anhydrous MgSO4 and the solvent was removed un-
der reduced pressure. The residue was purified by silica gel column
chromatography (n-hexane:AcOEt = 5:1) to afford 11 as a colorless
less crystals. Mp 165–167 °C; ½a D25
ꢃ
¼ þ25:6 (c 0.5, CHCl3); IR (KBr)
m
= 3324, 3013, 1746, 1736, 1690, 1655 cmꢁ1
;
1H NMR (300 MHz,
oil (151 mg, 65%). ½a D25
ꢃ
¼ þ51:3 (c 1.2, CHCl3, >99% ee); IR (neat)
CDCl3) d = 7.79 (br s, 1H), 5.91 (br s, 1H), 4.30 (d, J = 6.6 Hz, 1H),
3.76 (s, 3H), 3.70 (s, 3H), 2.21–1.42 (m, 22H); 13C NMR (75 MHz,
CDCl3) d = 175.3, 173.6, 159.8, 156.5, 66.8, 58.0, 56.6, 55.9, 52.8,
52.1, 35.3, 29.5, 28.4, 27.1, 25.4, 24.0, 23.6, 16.9, 14.7; [HR-
m ;
= 2948, 1721, 1701 cmꢁ1 1H NMR (300 MHz, CDCl3) d = 8.02 (d,
J = 7.2 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 4.71
(s, 2H), 4.38 (br s, 1H), 3.69 (s, 3H), 2.15–1.45 (m, 10H); 13C NMR
(75 MHz, CDCl3) d = 166.3, 154.9, 132.9, 130.3, 129.6, 128.3, 68.9,

2664
Y. Demizu et al. / Tetrahedron: Asymmetry 19 (2008) 2659–2665
64.1, 57.5, 52.1, 33.0, 32.3, 30.1, 25.7, 17.6; [HR-EI(+)]: m/z calcd for
4.3.9. Methyl N-[(1R)-N-methoxycarbonyl-8-azabicyclo[3.2.1]
octane-1-carbonyl]- -phenylglycinate 14d
C17H21NO4 [M]+ 303.1471: found 303.1470.
D
Compound 14d was prepared in a method similar to that de-
scribed for the preparation of 14a (1.6 mmol scale). 478 mg, 83%
4.3.4. (1R)-Benzoyloxymethyl-8-azabicyclo[3.2.1]octane 12
Compound 12 was prepared in a method similar to that de-
scribed for the preparation of 9 (0.5 mmol scale). 122 mg, 99%
yield; colorless oil; ½a D25
ꢃ
¼ þ74:7 (c 0.9, CHCl3, >99% ee); IR (neat)
m
= 3300, 2954, 1717, 1699, 1684 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
yield; colorless oil; ½a D25
ꢃ
¼ þ1:4 (c 0.6, CHCl3, >99% ee); IR (neat)
d = 7.39–7.28 (m, 5H), 6.94 (br s, 0.4H), 6.65 (d, J = 6.9 Hz, 0.6H),
5.59 (t, J = 7.0 Hz, 1H), 4.34 (br s, 1H), 3.73–3.35 (m, 6H), 2.35–
1.59 (m, 10H); 13C NMR (75 MHz, CDCl3) d = 172.5, 171.5, 155.9,
128.9, 128.8, 128.5, 127.5, 127.1, 66.2, 58.4, 58.1, 56.1, 52.6, 52.3,
36.3, 28.8, 26.8, 16.9; [HR-EI(+)]: m/z calcd for C19H24N2O5 [M]+
360.1685: found 360.1677.
m
= 3226, 2938, 1721 cmꢁ1 1H NMR (300 MHz, CDCl3) d = 8.05 (d,
;
J = 7.5 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 4.34
(dd, J = 11.1, 7.8 Hz, 2H), 3.55–3.78 (m, 1H), 2.40 (br s, 1H), 1.96–
1.33 (m, 10H); [HR-EI(+)]: m/z calcd for C15H19NO2 [M]+
245.1416: found 245.1410.
4.3.5. (1R)-Benzoyloxymethyl-8-azabicyclo[3.2.1]octane-N-oxyl
13
4.3.10. (1R)-N-Phenylcarbamoyl-8-azabicyclo[3.2.1]octane 15a
Compound 15a was prepared in a method similar to that de-
scribed for the preparation of 9 (0.5 mmol scale). 59 mg, 51% yield;
Compound 13 was prepared in a method similar to that de-
scribed for the preparation of 10 (0.4 mmol scale). 50 mg, 48%
colorless oil; ½a D27
ꢃ
¼ þ74:6 (c 0.6, CHCl3, >99% ee); IR (neat)
yield; red foam; ½a D24
ꢃ
¼ þ48:8 (c 1.0, CHCl3, >99% ee); IR (neat)
m ;
= 3314, 3278, 2928, 1665 cmꢁ1 1H NMR (300 MHz, CDCl3)
m
= 2955, 1725 cmꢁ1; [HR-EI(+)]: m/z calcd for C15H18NO3 [M]+
d = 9.01 (br s, 1H), 7.58 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 6.9 Hz, 2H),
7.07 (t, J = 7.0 Hz, 1H), 3.67–3.65 (m, 1H), 2.31–1.40 (m, 11H);
[HR-FAB(+)]: m/z calcd for C14H19N2O [M+H]+ 231.1498: found
231.1497.
260.1287: found 260.1272.
4.3.6. (1R)-N-Methoxycarbonyl-1-N-phenylcarbamoyl-8-
azabicyclo[3.2.1]octane 14a
4.3.11. (1R)-N-Benzylcarbamoyl-8-azabicyclo[3.2.1]octane 15b
Compound 15b was prepared in a method similar to that de-
scribed for the preparation of 9 (0.8 mmol scale). 144 mg, 74%
A solution of aniline (109 lL, 1.2 mmol), 7 (213 mg, 1.0 mmol),
EDC (230 mg, 1.2 mmol), and HOBt (162 mg, 1.2 mmol) in MeCN
(10 mL) was stirred at 60 °C for 24 h, and then volatiles were
evaporated. The residue was diluted with AcOEt, washed with
cold 3% aqueous HCl and 5% aqueous NaHCO3, and dried over
anhydrous MgSO4. After removal of solvent, the residue was puri-
fied by column chromatography on silica gel (n-hex-
ane:AcOEt = 3:1) to give 14a (202 mg, 70%) as colorless crystals.
yield; colorless oil; ½a D28
ꢃ
¼ þ28:2 (c 0.6, CHCl3, >99% ee); IR (neat)
m
= 3320, 3252, 2928, 1715, 1659 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d = 7.33–7.20 (m, 6H), 4.43 (d, J = 9.0 Hz, 2H), 3.57–3.55 (m, 1H),
2.27–1.40 (m, 11H); [HR-FAB(+)]: m/z calcd for C15H21N2O
[M+H]+ 245.1654: found 245.1647.
Mp 150–152 °C; ½a D18
ꢃ
¼ þ71:6 (c 1.0, CHCl3, >99% ee); IR (KBr)
= 3280, 2951, 1700, 1680 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
4.3.12. Methyl N-[(1R)-8-azabicyclo[3.2.1]octane-1-carbonyl]-
m
L-phenylglycinate 15c
d = 7.60 (br s, 1H), 7.50 (d, J = 7.5 Hz, 2H), 7.31 (t, J = 6.3 Hz, 2H),
7.08 (t, J = 7.0 Hz, 1H), 4.39 (br s, 1H), 3.70 (s, 3H), 2.24–1.41
(m, 10H); 13C NMR (100 MHz, CDCl3) d = 171.1, 156.1, 138.0,
128.9, 123.9, 119.8, 67.0, 58.3, 52.8, 35.9, 28.7, 26.9, 16.9; [HR-
FAB(+)]: m/z calcd for C16H21N2O3 [M+H]+ 289.1552: found
289.1559.
Compound 15c was prepared in a method similar to that de-
scribed for the preparation of 9 (1.2 mmol scale). 340 mg, 86%
yield; colorless oil; ½a D24
ꢃ
¼ þ0:8 (c 0.6, CHCl3, >99% ee); IR (neat)
m
= 3366, 3277, 2930, 1748, 1676 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d = 7.93 (d, J = 7.2 Hz, 0.5H), 7.83 (d, J = 7.2 Hz, 0.5H), 7.37–7.25 (m,
5H), 5.53 (t, J = 6.9 Hz, 1H), 3.72 (s, 3H), 3.69–3.57 (m, 1H), 2.25–
1.32 (m, 11H); [HR-EI(+)]: m/z calcd for C17H22N2O3 [M]+
302.1630: found 302.1614.
4.3.7. (1R)-N-Methoxycarbonyl-1-N-benzylcarbamoyl-8-
azabicyclo[3.2.1]octane 14b
Compound 14b was prepared in a method similar to that de-
scribed for the preparation of 14a (1.0 mmol scale). 235 mg, 78%
4.3.13. Methyl N-[(1R)-8-azabicyclo[3.2.1]octane-1-carbonyl]-
D-phenylglycinate 15d
yield; colorless crystals; Mp 126–128 °C; ½a D25
ꢃ
¼ þ70:8 (c 1.0,
Compound 15d was prepared in a method similar to that de-
CHCl3, >99% ee); IR (KBr)
m ;
= 3280, 2950, 1701, 1660 cmꢁ1 1H
scribed for the preparation of 9 (1.3 mmol scale). 328 mg, 83%
NMR (300 MHz, CDCl3) d = 7.31–7.22 (m, 5H), 6.14 (br s, 1H),
4.45 (br s, 2H), 4.29 (br s, 1H), 3.60 (s, 3H), 2.12–1.36 (m, 10H);
13C NMR (100 MHz, CDCl3) d = 173.0, 155.9, 138.5, 129.4, 128.5,
128.0, 127.3, 100.5, 66.4, 58.2, 52.4, 43.5, 36.3, 28.9, 26.8, 17.0;
[HR-FAB(+)]: m/z calcd for C17H23N2O3 [M+H]+ 303.1708: found
303.1712.
yield; Colorless oil; ½a D20
ꢃ
¼ þ1:4 (c 0.6, CHCl3, >99% ee); IR (neat)
m
= 3226 (br), 2938, 1721 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d = 7.86 (d, J = 7.2 Hz, 0.4H), 7.77 (d, J = 7.2 Hz, 0.6H), 7.32–7.22
(m, 5H), 5.46 (t, J = 7.0 Hz, 1H), 3.64 (s, 3H), 3.55–3.41 (m, 1H),
2.09–1.26 (m, 11H); [HR-EI(+)]: m/z calcd for C17H22N2O3 [M]+
302.1630: found 302.1628.
4.3.8. Methyl N-[(1R)-N-methoxycarbonyl-8-azabicyclo[3.2.1]
octane-1-carbonyl]-L-phenylglycinate 14c
4.3.14. (1R)-N-Phenylcarbamoyl-8-azabicyclo[3.2.1]octane-N-
oxyl 16a
Compound 14c was prepared in a method similar to that de-
scribed for the preparation of 14a (1.6 mmol scale). 449 mg, 78%
Compound 16a was prepared in a method similar to that de-
scribed for the preparation of 10 (0.2 mmol scale). 42 mg, 85%
yield; colorless oil; ½a D25
ꢃ
¼ þ53:0 (c 0.9, CHCl3, >99% ee); IR (neat)
yield; red foam; ½a D29
¼ þ72:1 (c 0.9, CHCl3, >99% ee); IR (neat)
ꢃ
= 2953, 1744, 1702, 1682 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
m
= 3256, 2953, 1686, 1447 cmꢁ1; [HR-FAB(+)]: m/z calcd for
m
C14H18N2O2 [M+H]+ 246.1369: found 246.1366.
d = 7.38–7.28 (m, 5H), 6.94 (br s, 0.6H), 6.65 (d, J = 7.5 Hz, 0.4H),
5.59 (t, J = 7.0 Hz, 1H), 4.34 (br s, 1H), 3.74–3.36 (m, 6H), 2.34–
1.58 (m, 10H); 13C NMR (75 MHz, CDCl3) d = 172.5, 171.3, 155.9,
128.9, 128.8, 128.3, 127.5, 127.1, 66.3, 58.3, 58.2, 56.1, 52.7, 52.3,
36.1, 28.8, 26.8, 17.0; [HR-EI(+)]: m/z calcd for C19H24N2O5 [M]+
360.1685: found 360.1693.
4.3.15. (1R)-N-Benzylcarbamoyl-8-azabicyclo[3.2.1]octane-N-
oxyl 16b
Compound 16b was prepared in a method similar to that de-
scribed for the preparation of 10 (0.6 mmol scale). 127 mg, 82%

Y. Demizu et al. / Tetrahedron: Asymmetry 19 (2008) 2659–2665
2665
yield; red foam; ½a D29
ꢃ
¼ þ18:7 (c 0.6, CHCl3, >99% ee); IR (neat)
The enantiomeric purity of (S)-24 was determined by chiral
HPLC: Daicel Chiralcel OD-H column (4.6 mm/, 250 mm), n-hex-
ane:2-propanol = 50:1, wavelength: 254 nm, flow rate: 0.5 mL/
min, retention time: 21.0 min for (S)-24, 22.5 min for (R)-24.
m
= 3270, 2951, 1721, 1650, 1478 cmꢁ1; [HR-FAB(+)]: m/z calcd
for C15H20N2O2 [M+H]+ 260.1525: found 260.1500.
4.3.16. Methyl N-[(1R)-8-azabicyclo[3.2.1]octane-1-carbonyl]-
phenylglycinate-N-oxyl 16c
L-
Acknowledgments
Compound 16c was prepared in a method similar to that de-
scribed for the preparation of 10 (1.1 mmol scale). 300 mg, 86%
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
Taisho Award in Synthetic Organic Chemistry, Japan.
yield; red oil; ½a D25
¼ þ86:1 (c 0.8, CHCl3, >99% ee); IR (neat)
ꢃ
m
= 3283, 2953, 1745, 1674 cmꢁ1
; [HR-EI(+)]: m/z calcd for
C17H21N2O4 [M]+ 317.1501: found 317.1511.
4.3.17. Methyl N-[(1R)-8-azabicyclo[3.2.1]octane-1-carbonyl]-
References
D
-phenylglycinate-N-oxyl 16d
Compound 16d was prepared in a method similar to that de-
1. (a) Maity, P.; König, B. Biopolymers (Pept. Sci.) 2008, 90, 8–27; (b) Tanaka, M.
Chem. Pham. Bull. 2007, 55, 349–358.
scribed for the preparation of 10 (1.0 mmol scale). 216 mg, 68%
yield; red oil; ½a D25
¼ þ119:7 (c 1.3, CHCl3, >99% ee); IR (neat)
ꢃ
2. (a) Cabrera, S.; Reyes, E.; Alemán, J.; Milelli, A.; Kobbelgaard, S.; Jørgensen, K. A.
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C. Tetrahedron: Asymmetry 2004, 15, 811–819; (c) Gil, A. M.; Buñuel, E.; Díaz-
de-Villegas, M. D.; Cativiela, C. Tetrahedron: Asymmetry 2003, 14, 1479–1488;
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11635–11644.
7. The synthesis of racemic proline analogue A1 has been recently reported:
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8. (a) Shiigi, H.; Mori, H.; Tanaka, T.; Demizu, Y.; Onomura, O. Tetrahedron Lett.
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I. L.; Maki, T.; Onomura, O. Tetrahedron Lett. 2000, 41, 4619–4622; (b)
Matsumura, Y.; Kinoshita, T.; Yanagihara, Y.; Kanemoto, N.; Watanabe, M.
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m
= 3277, 2955, 1746, 1676 cmꢁ1
; [HR-EI(+)]: m/z calcd for
C17H21N2O4 [M]+ 317.1501: found 317.1488.
4.4. General procedure for the enantioselective electrooxidation
of DL-sec-alcohols 17, 19–24 with N-oxyls 10, 13, and 16a–d
Anodic oxidation of DL-1-phenylethanol DL-17 was carried out
using platinum electrodes (1 cm ꢂ 2 cm) in an undivided beaker-
type cell. DL-17 (61 mg, 0.5 mmol), 10 (9.2 mg, 0.05 mmol), and
NaBr (206 mg, 2.0 mmol) were then 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 a constant current
(20 mA) at 0 °C, the mixture was poured into water and was ex-
tracted with AcOEt (20 mL ꢂ 3). The combined organic layer was
dried over anhydrous MgSO4 and the solvent was removed un-
der reduced pressure. The residue was purified by silica gel col-
umn chromatography (n-hexane:AcOEt = 10:1) to afford
acetophenone 18 (35.4 mg, 59% yield) and (S)-17 (24.6 mg, 41%
yield) as a colorless oil.
The enantiomeric purity of (S)-17 was determined by chiral
HPLC: Daicel Chiralcel OB column (4.6 mmu, 250 mm), n-hex-
ane:2-propanol = 15:1, wavelength: 254 nm, flow rate: 0.5 mL/
min, retention time: 13.5 min for (S)-17, 17.5 min for (R)-17.
The enantiomeric purity of (S)-19 was determined by chiral
HPLC: Daicel Chiralcel OB column (4.6 mm/, 250 mm), n-hex-
ane:2-propanol = 15:1, wavelength: 254 nm/, flow rate: 0.5 mL/
min, retention time: 11.9 min for (S)-19, 16.9 min for (R)-19.
The enantiomeric purity of (S)-20 was determined by chiral
HPLC: Daicel Chiralcel AD column (4.6 mm/, 250 mm), n-hex-
ane:2-propanol = 100:1, wavelength: 254 nm, flow rate: 1.0 mL/
min, retention time: 14.0 min for (R)-20, 16.5 min for (S)-20.
The enantiomeric purity of (S)-21 was determined by chiral
HPLC: Daicel Chiralcel OJ column (4.6 mm/, 250 mm), n-hex-
ane:2-propanol = 9:1, wavelength: 254 nm, flow rate: 1.0 mL/min,
retention time: 13.8 min for (S)-21, 16.8 min for (R)-21.
12. Crystallographic data for structure of tripeptide 8 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication number
CCDC 699629. Copies of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB21EZ, UK; fax: +44(0) 1223 336033 or e-
mail: deposit@ccdc.cam.ac.uk.
13. Ravi, A.; Balaram, P. Tetrahedron 1984, 40, 2577–2583.
14. Cyclic voltammogram for 10 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 10: 1.0 mM.
Scan rate: 30 mV/s. Cyclic voltammogram for other N-oxyls showed reversible
wave pattern similar to that for 10. Oxidation potential: 0.83 V for 10, 0.82 V
for 13, 0.58 V for 16a, 0.79 V for 16b, 0.78 V for 16c, 0.80 V for 16d.
15. (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.
16. Kagan, H. B.; Fiaud, J. C.. In Topics in Stereochemistry; Eliel, E. L., Ed.; Wiley &
Sons: New York, 1988; Vol. 18, pp 249–330.
The enantiomeric purity of (S)-22 was determined by chiral
HPLC: Daicel Chiralcel OJ column (4.6 mm/, 250 mm), n-hex-
ane:2-propanol = 9:1, wavelength: 254 nm, flow rate: 1.0 mL/min,
retention time: 12.7 min for (S)-22, 16.0 min for (R)-22.
The enantiomeric purity of (S)-23 was determined by chiral
HPLC: Daicel Chiralcel OB column (4.6 mm/, 250 mm), n-hex-
ane:2-propanol = 15:1, wavelength: 254 nm, flow rate: 1.0 mL/
min, retention time: 15.0 min for (R)-23, 27.0 min for (S)-23.