Stereodivergent approach to both syn- and anti-isomers of γ-amino-β-hydroxy acids: (3S,4S)- and (3R,4S)-AHPPA derivatives

Article abstract of DOI:10.1016/j.tetasy.2011.09.021

A stereodivergent approach employing an N-hydroxymethyl group has been utilized to produce both diastereomeric derivatives of (3S,4S)-AHPPA 3 and (3R,4S)-AHPPA 4, via an intramolecular conjugate addition and an intramolecular epoxidation, respectively. Th

Full text of DOI:10.1016/j.tetasy.2011.09.021

Tetrahedron: Asymmetry 22 (2011) 1700–1704
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Tetrahedron: Asymmetry
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Stereodivergent approach to both syn- and anti-isomers of
c-amino-b-hydroxy acids: (3S,4S)- and (3R,4S)-AHPPA derivatives
⇑
Dongwon Yoo, Jeeyun Song, Moon Sung Kang, Eun-Sil Kang, Young Gyu Kim
Department of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereodivergent approach employing an N-hydroxymethyl group has been utilized to produce both dia-
stereomeric derivatives of (3S,4S)-AHPPA 3 and (3R,4S)-AHPPA 4, via an intramolecular conjugate addi-
tion and an intramolecular epoxidation, respectively. The selectivity of the intramolecular conjugate
addition was more than 10:1 while that of the intramolecular epoxidation was more than 1:20.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 5 September 2011
Accepted 30 September 2011
Available online 3 November 2011
1. Introduction
NH2
NH
Bn
CO2H
CO2H
Bn
CO2H
CO2H
c
-Amino-b-hydroxy acids are frequent motifs found in a num-
OH
OH
ber of natural and synthetic compounds with various biological
activities. As a result, the stereoselective syntheses of these com-
pounds have attracted a lot of attention.1 Among others, both the
syn- and anti-isomers of 4-amino-3-hydroxy-5-phenylpentanoic
acid (AHPPA) are of natural occurrence as key constituents of phar-
maceutically important molecules. Compound (3S,4S)-AHPPA 1 is a
common constituent of many biologically active compounds such
as the ahpatinins, tasiamide B, thalassospiramide B, and other pro-
tease inhibitors (Fig. 1).2 Meanwhile, N-methyl-(3R,4S)-AHPPA 2 is
an amino acid constituent of hapalosin, which has multidrug-resis-
tance reversing activity in cancer cells.3
1
2
Boc
Bn
Boc
Bn
NH
NH
OH
OH
3
4
Figure 1. (3S,4S)-AHPPA, (3R,4S)-AHPPA, and their derivatives.
Due to their potential biological activities, considerable effort
toward the asymmetric synthesis of AHPPA derivatives has been
expended, most of which employ separate routes to obtain each
diastereomer of AHPPAs.4,5
2. Results and discussion
The key intermediate 5 for our stereodivergent approach,
containing the N-hydroxymethyl group, was derived from N-Boc-
Thus, it would be interesting and useful to develop an efficient
and stereodivergent route to give both syn- and anti-stereoisomers
L
-phenylalanine in three steps by following a reported proce-
dure.7,8 The preparation of the syn-isomer, an N-Boc derivative of
(3S,4S)-AHPPA 3, was first started by the intramolecular conjugate
addition of 5 (Scheme 1). In terms of selectivity, this showed a pref-
erence for trans-oxazolidine 6 over the corresponding cis-isomer
with several bases. The best selectivity of more than 10:1, as deter-
mined by GC, was attained with 1.0 equiv of K2CO3 as a base at
1.0 M concentration. Other bases such as TEA, NaHCO3, and DBU
showed 1.7:1, 2.1:1, and 4.3:1 diastereoselectivity, respectively.
In addition, higher concentrations of base lowered the yield, caus-
ing partial hydrolysis of ester 6 to give the corresponding carbox-
ylic acid as a by-product.
Orthogonal deprotection of the N,O-acetal group of 6 in the
presence of other protecting groups was difficult under acidic or
basic hydrolysis conditions. Therefore, we turned our attention to
oxidative cleavage conditions and the N,O-methylene group of 6
was selectively converted into the O-formyl group of 7 via
of the c-amino-b-hydroxy acid units from a common starting com-
pound.6 We have demonstrated that the N-hydroxymethyl group
can be used as an internal nucleophile for the b-hydroxyl group
of (ꢀ)-statine and the b-amino group of (ꢀ)-3-aminodeoxystatine7
as well as a configurational stabilizer of
a
-amino aldehydes.8 We
have also reported that the N-hydroxymethyl group can be utilized
to accomplish anti-selective epoxidation via functional group
transformation.9 Herein, we report a stereodivergent and stereose-
lective synthetic methodology for both the syn- and anti-stereoiso-
mers of AHPPA derivatives 3 and 4 via intramolecular conjugate
addition and epoxidation, respectively.
⇑
Corresponding author. Tel.: +82 2 880 8347; fax: +82 2 885 6989.
E-mail address: ygkim@snu.ac.kr (Y. G. Kim).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.09.021

D. Yoo et al. / Tetrahedron: Asymmetry 22 (2011) 1700–1704
1701
Ru-catalyzed oxidation10 along with the corresponding oxazolidi-
none11 as a by-product in a ratio of ca. 4:1 (1H NMR). A diastereo-
meric mixture of 7 (syn-isomer) and its anti-isomer (not shown)
was not separable by column chromatography, but 8 (syn-isomer)
was isolable from its anti-isomer (not shown). Thus, 8 could be ob-
tained as a single diastereomer after removing the O-formyl group
under acidic conditions, followed by column chromatography sep-
aration. The synthesis of N-Boc-(3S,4S)-AHPPA 3 was completed
with the basic hydrolysis of methyl ester 8. The physical properties
(melting point, specific rotation) and spectroscopic data of 3
matched those in the literature.6b,12
A complementary pathway for the preparation of the anti-iso-
mer, an N-Boc derivative of (3R,4S)-AHPPA 4, is also shown in
Scheme 1. Starting from the common intermediate 5, anti-selective
intramolecular epoxidation was employed to result in the opposite
configuration of the b-hydroxyl group. After acetylation of the N-
hydroxymethyl group of 5, the N-hydroperoxymethyl group of 9
was introduced by treating the resulting acetate from 5 with aque-
ous H2O2 under acidic conditions for 4 h in the presence of MgSO4.
Without work-up of the resulting reaction mixture, the epoxida-
tion reaction was achieved within 30 min at room temperature
by the sequential addition of MeOH and K2CO3. It should be noted
that the epoxidation was very fast even under mild basic condi-
tions, probably because of the intramolecular nature of the reac-
tion. The N-hydroxymethyl group of 10 was removed via PDC
oxidation followed by methanolysis of 11. Thus, epoxide 12 was
obtained in 48% yield after five reactions from 5. The diastereose-
lectivity of the intramolecular epoxidation was determined at the
stage of 12, because the diastereomeric mixtures of 10 and 11
could not be well separated on the 1H NMR spectra. The ratio of
12 (anti-epoxide) and its syn-epoxide (not shown) was more than
20:1 by 1H NMR, indicating that the in situ intramolecular epoxida-
tion reaction gave the anti-epoxide with high selectivity. The epox-
idation selectivity did not depend much on the concentration of
hydroperoxide 9. However, the yields of the epoxidation decreased
as the concentration of hydroperoxide 9 increased. This could be
explained by the resulting epoxide 10 reacting further to give oxa-
zolidinone 14 which was presumably produced by in situ intramo-
lecular attack of the Boc group onto the epoxide ring in higher
concentrations (Scheme 2).9 The 1H NMR analysis of 14 showed a
J3,4 value of 4.2 Hz, which can be used as an additional evidence
for the anti-selective intramolecular epoxidation.11,12
A diastereomeric mixture of epoxide 12 (anti-isomer) and its
syn-epoxide (not shown) was then reduced regioselectively via
Pd-catalyzed hydrogenation to give the corresponding diastereo-
meric amino alcohol isomers,13 from which the major anti-diaste-
reomer 13 could be isolated from its syn-isomer by column
chromatography (Scheme 1). Initially, we tried to convert the
epoxide group of 10 directly into the b-hydroxyl group before re-
moval of the N-hydroxymethyl group of 10. However, those trials
were unsuccessful due to the instability of 10. Under the catalytic
hydrogenation conditions, 10 was cyclized to afford 14 as men-
tioned earlier (Scheme 2). After the removal of the N-hydroxy-
methyl group of 10, however, 12 was stable enough to undergo
regioselective reduction. Previously, the N-hydroxymethyl group
was easily removed under mild acidic or basic conditions.8,9 In
the presence of an epoxide however, 10 was transformed into oxa-
zolidine 15 under mild basic conditions via intramolecular attack
of the N-hydroxymethyl group at the epoxide, while oxazolidinone
14 was produced under mild acidic or even neutral conditions. In
the reduction of the epoxide of 12 into the alcohol of 13, the Pd cat-
alyst was most effective under 10 atm of H2 gas among the reduc-
ing reagents investigated; an Rh catalyst reduced the phenyl ring of
12, a Pt catalyst was not effective at all, while regioselective reduc-
tion with SmI2 resulted in the partial elimination of the hydroxyl
group of 13 to give the corresponding
a,b-unsaturated ester (not
shown). A low yield of 13 (43%) was obtained with the Pd catalyst
under 1 atm of H2 gas and some starting epoxide 12 was also
recovered (38%). Finally, the synthesis of N-Boc-(3R,4S)-AHPPA 4
was completed with basic hydrolysis of methyl ester 13 as
described above. The physical properties (melting point, specific
rotation) and spectroscopic data of 4 matched those in the
literature.6b,12
1. Ac2O, DMAP, TEA
Boc
Bn
Boc
Bn
CH2Cl2, 98%
N
OH
CO2Me
N
OOH
CO2Me
2. 30% H2O2, DME
cat. p-TsOH
MgSO4
O
5
9
Boc
HN
N
OH
CO2Me
MeOH
76%
O
3
K2CO3, MeOH
77% (2 steps)
K2CO3, MeOH
92%
4
Bn
Bn
O
CO2Me
Boc
Bn
HO
Boc
Bn
10
N
N
OH
J3,4 = 4.2 Hz
O
14
CO2Me
O
K2CO3, MeOH
80%
6
CO2Me
10 (95% dr)
(91% dr)
RuCl3, t-BuOOH
PhH, 77%
PDC, CH2Cl2
86%
Boc
Bn
N
O
Boc
Bn
Boc
Bn
NR2
NH
CO2Me
HO
15
CO2Me
OCHO
CO2Me
O
11 R22=CHO (95% dr)
K2CO3
7 (91% dr)
p-TsOH
MeOH, 82%
MeOH
12
Scheme 2. Facile cyclization of 10 into 14 or 15.
R =H (95% dr)
71%
Pd/C, EtOAc
H2, 72%
3. Conclusion
Boc
Bn
Boc
NH
NH
CO2R1
Bn
CO2R3
In conclusion, we have established a stereodivergent and stere-
oselective synthetic method to obtain both syn- and anti deriva-
tives of 4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA), 3
and 4, from a readily available and common starting compound,
OH
OH
8 R11=Me
13
3
R =Me
NaOH, H2O
THF, 81%
NaOH, H2O
THF, 76%
4 R3=H
3
R =H
c-amino-a,b-unsaturated ester 5. The intramolecular conjugate
addition of the N-hydroxymethyl group of unsaturated ester 5
Scheme 1. Synthesis of N-Boc-(3S,4S)-AHPPA 3 and N-Boc-(3R,4S)-AHPPA 4.

1702
D. Yoo et al. / Tetrahedron: Asymmetry 22 (2011) 1700–1704
resulted in the syn-selectivity of the b-hydroxyl group, whereas the
complementary anti-selectivity of the b-hydroxyl group was estab-
lished from the intramolecular epoxidation of the N-hydroper-
oxymethyl group of unsaturated ester 9. Thus, both (3S,4S)-
AHPPA and (3R,4S)-AHPPA diastereomers were obtained as their
Boc protected forms in 47% (4 steps) and 25% (7 steps) yields from
5, respectively. We hope that the method could provide a versatile
J = 15.5, and 5.4), 2.45 (dd, 1H, J = 15.5, and 7.7), 2.80 (dd, 1H,
J = 13.3, and 8.2), 3.12 (dd, 1H, J = 13.3, and 3.9), 3.59 (s, 3H),
3.84–3.89 (m, 1H), 4.30–4.35 (m, 1H), 4.59 (d, 1H, J = 4.2), 5.05
(m, 1H), 7.18–7.31 (m, 5H); 13C NMR d 28.3, 38.0, 38.8, 51.8,
60.8, 77.9, 78.7, 80.5, 126.6, 128.6, 129.4, 137.0, 152.8, 170.5;
HRMS(CI) calcd for C18H26NO5 (M+ꢀH) 336.1811, found 336.1811.
approach for the synthesis of either diastereomer of
droxy acids found in natural products.
c-amino-b-hy-
4.2.3. Methyl (3S,4S)-3-O-formyl-4-(tert-butoxycarbonyl)-
amino-5-phenylpentanoate 7
To a mixture of 6 and its cis-isomer (78 mg, 0.23 mmol) in ben-
zene (5 mL) was added RuCl3 monohydrate (4.82 mg, 0.02 mmol)
and a 5 M solution of TBHP in decane (1.88 mL, 9.32 mmol). The
reaction mixture was stirred for 7 h at room temperature and then
partitioned between H2O (2 ꢁ 20 mL) and Et2O (2 ꢁ 20 mL). The
combined organic layers were dried over MgSO4, filtered, and con-
centrated under reduced pressure. The residue was purified with
SiO2 column chromatography (2:1 hexane/EtOAc) to give the for-
mate 7 containing its anti-isomer (63 mg, 77%) in a ratio of more
than 10:1 and the corresponding oxazolidinone11 (16 mg, 19%) as
a colorless oil. Data for 7 (syn-isomer): 1H NMR d 1.37 (s, 9H),
2.60–2.83 (m, 4H), 3.65 (s, 3H), 4.11–4.19 (m, 1H), 4.70 (br d, 1H,
J = 10.1), 5.33–5.40 (m, 1H), 7.17–7.32 (m, 5H), 8.11 (s, 1H); 13C
NMR d 28.2, 36.6, 38.8, 52.0, 53.7, 71.0, 79.8, 126.8, 128.6, 129.1,
136.8, 155.5, 160.1, 170.3; HRMS(CI) calcd for C18H26NO6 (M++H)
352.1760, found 352.1761.
4. Experimental
4.1. General
Materials were obtained from commercial suppliers and were
used without further purification. Methylene chloride was distilled
from calcium hydride immediately prior to use. Likewise benzene
was distilled from sodium benzophenone ketyl. Air or moisture
sensitive reactions were conducted under nitrogen atmosphere
using oven-dried glassware and the standard syringe/septa tech-
nique. The reactions were monitored with a SiO2 TLC plate under
UV light (254 nm) followed by visualization with a molybdenum
stain solution. Column chromatography was performed on Silica
Gel 60 (70–230 mesh). 1H NMR spectra were measured at
300 MHz in CDCl3 unless otherwise stated and data were reported
as follows in ppm (d) from the internal standard (TMS, 0.0 ppm):
chemical shift (multiplicity, integration, coupling constant in Hz).
Gas chromatographic analyses were done with a capillary column
(30 m ꢁ 0.25 mm). High resolution mass spectra were obtained
4.2.4. Methyl (3S,4S)-N-tert-butoxycarbonyl-4-amino-3-
hydroxy-5-phenylpentanoate 8
To a diastereomeric mixture of formate 7 and its anti-isomer
(71 mg, 0.20 mmol) in MeOH (4 mL) was added p-TsOH (38 mg,
0.20 mmol). The mixture was stirred for 1 h at room temperature.
The resulting mixture was partitioned between H2O (2 ꢁ 10 mL)
and Et2O (2 ꢁ 10 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure. The res-
idue was purified with SiO2 column chromatography (4:1 hexane/
EtOAc) to give 8 (54 mg, 82%) as a white solid. Rf = 0.26 (2:1 hex-
with
a
JEOL JMS-AX505WA gas chromatography–mass
spectrometer.
4.2. Synthesis of N-Boc-(3S,4S)-AHPPA 3 [(3S,4S)-N-tert-buth-
oxycarbonyl-4-amino-3-hydroxy-5-phenylpentanoic acid]
4.2.1. Methyl (2E,4S)-4-(N-tert-butoxycarbonyl-N-hydroxy-
methyl)amino-5-phenylpent-2-enoate 5
ane/EtOAc); mp 92–94 °C {lit.4a mp 97–98 °C}; ½a 2D0
¼ ꢀ36:5 (c
ꢂ
To
a solution of (4S)-4-benzyl-3-(tert-butoxycarbonyl)-5-
0.1, CH3OH) {lit.4a
½
a 2D0
ꢂ
¼ ꢀ36 (c 1.0, CH3OH)}; 1H NMR d 1.41 (s,
hydroxyoxazolidine8a (1.66 g, 5.95 mmol) in benzene (100 mL)
was added methyl (triphenylphosphoranylidene)acetate (2.39 g,
7.14 mmol). The mixture was heated at reflux for 2 h. The resulting
mixture was partitioned between H2O (2 ꢁ 100 mL) and Et2O
(2 ꢁ 100 mL). The combined organic layers were dried with MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified with SiO2 column chromatography (4:1 hexane/EtOAc) to
give 5 (2.00 g, 94%) as a colorless oil. Rf = 0.29 (2:1 hexane/EtOAc);
9H), 2.39 (dd, 1H, J = 17.0, and 2.6), 2.60 (dd, 1H, J = 17.0, and
10.1), 2.92 (d, 2H, J = 7.7), 3.44 (d, 1H, J = 2.8), 3.68 (s, 3H), 3.72–
3.77 (m, 1H), 3.94–4.02 (m, 1H), 4.95 (d, 1H, J = 9.3), 7.12–7.35
(m, 5H); 13C NMR d 28.3, 38.3, 38.6, 51.9, 55.3, 66.9, 79.5, 126.4,
128.5, 129.4, 138.1, 155.8, 174.0; HRMS calcd for C17H26NO5
(M++H) 324.1811, found 324.1810.
½
a 1D9
ꢂ
¼ ꢀ36:7 (c 1.74, CHCl3); 1H NMR (CD3OD) d 1.42 (s, 9H), 2.87–
4.2.5. (3S,4S)-N-tert-Buthoxycarbonyl-4-amino-3-hydroxy-5-
phenylpentanoic acid 3
3.12 (m, 2H), 3.74 (s, 3H), 4.47–4.61 (m, 1H), 4.77–4.83 (m, 2H),
5.97 (d, 1H, J = 15.9), 7.01 (dd, 1H, J = 15.9, and 5.0), 7.19–7.32
(m, 5H); 13C NMR d 27.7, 38.3, 51.1, 58.6, 69.6, 80.5, 121.1, 126.1,
128.0, 128.8, 137.3, 147.1, 154.8, 166.2.
To a solution of 8 (186 mg, 0.53 mmol) in THF (5 mL) and H2O
(5 mL) was added NaOH (128 mg, 3.2 mmol). The mixture was stir-
red for 1 h at room temperature. Then a cold aq solution of 1 M HCl
(5 mL) was added to the resulting solution and the mixture was
partitioned between H2O (2 ꢁ 20 mL) and EtOAc (2 ꢁ 20 mL). The
combined organic layers were dried over MgSO4, filtered, and con-
centrated under reduced pressure. The solid residue was purified
with SiO2 column chromatography (95:5:1 CH2Cl2/MeOH/AcOH)
to give 3 (133 mg, 81%) as a white solid. Rf = 0.22 (95:5:1 CH2Cl2/
4.2.2. Methyl (4S,5S)-(4-benzyl-3-tert-butoxycarbonyl-oxa-
zolidin-5-yl)acetate 6
To a solution of 5 (574 mg, 1.71 mmol) in MeOH (1.7 mL) was
added K2CO3 (237 mg, 1.71 mmol) at room temperature and the
mixture was stirred for 30 min. Then a cold aq solution of 1 M
HCl (3 mL) was added to the resulting solution and the mixture
was partitioned between H2O (2 ꢁ 20 mL) and Et2O (2 ꢁ 20 mL).
The combined organic layers were dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was puri-
fied with SiO2 column chromatography (4:1 hexane/EtOAc) to give
a mixture of 6 and its cis-isomer (527 mg, 92%) as a colorless oil in
a ratio of more than 10:1. Data for 6 (trans-isomer): Rf = 0.35 (2:1
hexane/EtOAc); 1H NMR (60 °C) d 1.47 (s, 9H), 2.22 (dd 1H,
MeOH/AcOH); mp 147–149 °C {lit.12 mp 148–148.5 °C}; ½a 2D0
¼
ꢂ
ꢀ36:8 (c 0.05, CH3OH) {lit.12
½
a 2D0
ꢂ
¼ ꢀ37:0 (c 1.1, CH3OH)}; 1H
NMR (CD3OD, 50 °C) d 1.35 (s, 9H), 2.35–2.49 (m, 2H), 2.72 (dd,
1H, J = 13.6, and 9.0), 2.88 (dd, 1H, J = 13.6, and 6.0), 3.74–3.79
(m, 1H), 4.03–4.12 (m, 1H), 7.13–7.24 (m, 5H); 13C NMR (CD3OD)
d 28.7, 38.8, 40.0, 57.3, 69.9, 80.1, 127.2, 129.3, 130.4, 140.1,
158.2, 175.5; IR (KBr) 3378, 2980, 1692, 1680 cmꢀ1; HRMS(CI)
calcd for C16H24NO5 (M++H) 310.1653, found 310.1654.

D. Yoo et al. / Tetrahedron: Asymmetry 22 (2011) 1700–1704
1703
4.3. Synthesis of N-Boc-(3R,4S)-AHPPA 4 [(3R,4S)-N-tert-buth-
oxycarbonyl-4-amino-3-hydroxy-5-phenylpentanoic acid]
was partitioned between H2O (2 ꢁ 20 mL) and Et2O (2 ꢁ 20 mL).
The combined organic layers were dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was puri-
fied with SiO2 column chromatography (2:1 hexane/EtOAc) to give
a mixture of 12 and its syn-isomer (419 mg, 71%) as a white solid in
a ratio of more than 20:1. Data for 12 (anti-isomer): Rf = 0.38 (2:1
hexane/EtOAc); mp 106–107 °C; 1H NMR (50 °C) d 1.39 (s, 9H), 2.85
(dd, 1H, J = 14.1, and 7.6), 2.96 (dd, 1H, J = 14.1, and 5.2), 3.16 (dd,
1H, J = 6.5, and 1.5), 3.49 (d, 1H, J = 1.5), 3.73–3.81 (m, 1H), 3.77 (s,
3H), 4.41 (br d, 1H, J = 7.8), 7.20–7.36 (m, 5H); 13C NMR (DMSO-d6)
d 28.1, 36.7, 50.1, 51.5, 52.2, 58.9, 78.0, 126.2, 128.1, 129.1, 137.9,
155.2, 168.9; IR (KBr) 3371, 2980, 1754, 1677, 1212 cmꢀ1; Anal.
Calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found: C, 63.54;
H, 7.39; N, 4.16; HRMS calcd for C17H24NO5 (M++H) 322.1654,
found 322.1654.
4.3.1. Methyl (2R,3S)-3-[(S)-1-(N-tert-butoxycarbonyl-N-hydroxy-
methyl)amino)-2-phenylethyl]-oxirane-2-carboxylate 10
To a solution of 5 (1.92 g, 5.72 mmol) in CH2Cl2 (80 mL) was
added Ac2O (1.75 g, 17.2 mmol), TEA (1.74 g, 17.2 mmol), and
DMAP (140 mg, 1.14 mmol). The mixture was stirred for 1 h at
room temperature. The resulting mixture was partitioned between
H2O (2 ꢁ 40 mL) and Et2O (2 ꢁ 40 mL). The combined organic lay-
ers were dried over MgSO4, filtered, and concentrated under re-
duced pressure. The residue was purified with SiO2 column
chromatography (2:1 hexane/EtOAc) to give the corresponding
acetate (2.11 g, 98%) as a colorless oil. Rf = 0.51 (2:1 hexane/
EtOAc); ½a 1D9
ꢂ
¼ ꢀ34:9 (c 0.32, CHCl3); 1H NMR d 1.43 (s, 9H), 1.99
(s, 3H), 2.99 (dd, 1H, J = 13.7, and 6.6), 3.01–3.19 (m, 1H), 3.74 (s,
3H), 4.55–4.95 (m, 1H), 5.04 (d, 1H, J = 10.9), 5.28 (br d, 1H,
J = 10.9), 5.89 (dd, 1H, J = 15.9, and 1.7), 7.01 (dd, 1H, J = 15.9, and
5.3), 7.10–7.36 (m, 5H); 13C NMR d 20.5, 27.7, 38.3, 51.1, 59.1,
69.6, 80.5, 121.1, 126.1, 128.0, 128.8, 137.3, 147.1, 154.8, 166.2,
170.7; Anal. Calcd for C20H27NO6: C, 63.64; H, 7.21; N, 3.71. Found:
C, 63.59; H, 7.31; N, 3.58. To a solution of the above acetate
(849 mg, 2.25 mmol) in DME (30 mL) was added 30% aq H2O2
(1.79 g, 16.0 mmol), p-TsOH (25 mg, 0.23 mmol), and MgSO4
(100 mg). The reaction mixture was stirred for 4 h at room temper-
ature. After filtration of MgSO4 from the resulting mixture, MeOH
(17 mL), and K2CO3 (933 mg, 6.75 mmol) were added in sequence
to the filtrate. The resulting mixture was stirred at room tempera-
ture and the reaction was complete within 30 min. The resulting
mixture was partitioned between H2O (2 ꢁ 30 mL) and Et2O
(2 ꢁ 30 mL). The combined organic layers were dried with MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified with SiO2 column chromatography (4:1 hexane/EtOAc) to
give a mixture of 10 and its syn-isomer (611 mg, 77%) as a colorless
oil in a ratio of more than 20:1. Data for 10 (anti-isomer): 1H NMR
(benzene-d6, 75 °C) d 1.29 (s, 9H), 2.81 (dd, 1H, J = 14.1, and 5.3),
2.87–3.00 (m, 1H), 3.29 (s, 3H), 3.45 (d, 1H, J = 1.8), 3.57–3.65 (m,
1H), 3.72–3.85 (m, 1H), 4.26–4.40 (m, 1H), 4.45–4.62 (m, 1H),
6.96–7.11 (m, 5H); 13C NMR (benzene-d6) d 28.9, 37.4, 52.2, 53.2,
60.3, 61.1, 71.8, 81.4, 127.4, 129.3, 130.1, 138.7, 155.6, 169.3; IR
(KBr) 3433, 1715, 1675 cmꢀ1. Compound 10 was rather reactive
and cyclized during storage at room temperature.9 Therefore, an
elemental analysis of 10 was not carried out. Rotational isomerism
of 10 blurred some of the NMR peaks.
4.3.3. Methyl (3R,4S)-N-tert-buthoxycarbonyl-4-amino-3-
hydroxy-5-phenylpentanoate 13
To a solution of 12 and its syn-isomer (173 mg, 0.54 mmol) in
ethyl acetate (12 mL) was added 5% palladium on carbon
(229 mg, 0.11 mmol). The solution was stirred under 10 atm of
H2 gas for 3 d at room temperature. The palladium catalyst was
then filtered off, and the filtrate was concentrated under reduced
pressure. The residue was purified with SiO2 chromatography
(hexane/EtOAc = 8:1) to give 13 (103 mg, 59%) as a white solid
(72% yield based on recovered starting materials). The unreacted
starting material (29 mg, 17%) was recovered and reused.
Rf = 0.16 (2:1 hexane/EtOAc); mp 118–120 °C; ½a D20
¼ ꢀ19:9 (c
ꢂ
0.2, CH3OH); 1H NMR d 1.35 (s, 9H), 2.51 (dd, 1H, J = 16.5, and
8.7), 2.53–2.62 (m, 1H), 2.84 (dd, 1H, J = 13.9, and 8.3), 2.97 (dd,
1H, J = 13.9, and 4.3), 3.59–3.69 (m, 1H), 3.72 (s, 3H), 3.77–3.82
(m, 1H), 3.94–4.05 (m, 1H), 4.52 (br d, 1H, J = 7.3), 7.17–7.33 (m,
5H); 13C NMR d 28.2, 35.8, 38.0, 51.9, 55.1, 70.0, 79.7, 126.5,
128.5, 129.5, 137.5, 155.8, 173.4; IR (KBr) 3359, 2981, 1741,
1686, 1255; HRMS calcd for C17H26NO5 (M++H) 324.1811, found
324.1810.
4.3.4. (3R,4S)-N-tert-Butoxycarbonyl-4-amino-3-hydroxy-5-
phenylpentanoic acid 4
To a solution of 13 (141 mg, 0.44 mmol) in THF (2 mL) and
H2O (2 mL) was added NaOH (52 mg, 1.31 mmol). The mixture
was stirred for 1 h at room temperature. Then, a cold aq solution
of 1 M HCl (3 mL) was added to the resulting mixture and the
mixture was partitioned between H2O (2 ꢁ 20 mL) and EtOAc
(2 ꢁ 20 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
solid residue was purified with SiO2 column chromatography
(95:5:1 CH2Cl2/MeOH/AcOH) to give 4 (103 mg, 76%) as a white
solid. Rf = 0.19 (95:5:1 CH2Cl2/MeOH/AcOH); mp 181–183 °C
4.3.2. Methyl (2R,3S)-3-[(S)-1-(N-tert-butoxycarbonylamino)-2-
phenylethyl]-oxirane-2-carboxylate 12
To a solution of 10 and its syn-isomer (1.10 g, 3.13 mmol) in
CH2Cl2 (50 mL) was added PDC (1.61 g, 4.27 mmol). The mixture
was stirred overnight at room temperature. The resulting mixture
was partitioned between H2O (2 ꢁ 40 mL) and Et2O (2 ꢁ 40 mL).
The combined organic layers were dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was puri-
fied with SiO2 column chromatography (2:1 hexane/EtOAc) to give
a mixture of 11 and its syn-isomer (939 mg, 86%) as a colorless oil
in a ratio of more than 20:1. Data for 11 (anti-isomer): 1H NMR d
1.45 (br s, 9H), 3.15 (dd, 1H, J = 13.8, and 5.6), 3.33 (d, 1H,
J = 1.8), 3.36 (dd, 1H, J = 13.8, and 11.0), 3.78 (s, 3H), 3.73–3.89
(m, 1H), 4.23–4.44 (m, 1H), 7.07–7.32 (m, 5H), 9.00 (s, 1H); 13C
NMR d 27.6, 35.3, 51.7, 52.2, 55.1, 57.7, 84.6, 126.6, 128.2, 128.8,
136.1, 151.4, 162.6, 168.3; Anal. Calcd for C18H23NO6: C, 61.88;
H, 6.64; N, 4.01. Found: C, 61.53; H, 6.72; N, 3.84. To a solution
of 11 and its syn-isomer (644 mg, 1.84 mmol) in MeOH (10 mL)
was added K2CO3 (255 mg, 1.84 mmol). The mixture was stirred
for 0.5 h at room temperature. Then, a cold aq solution of 1 M
HCl (5 mL) was added to the resulting solution and the mixture
{lit.6b mp 183–185 °C}; ½a 2D0
ꢂ
¼ ꢀ17:9 (c 0.024, CH3OH) {lit.6b
½
a 2D0
ꢂ
¼ ꢀ17:2 (c 1.4, CH3OH)}; 1H NMR (CD3OD) d 1.29 (s, 9H),
2.38 (dd, 1H, J = 15.5, and 9.2), 2.51–2.63 (m, 2H), 3.10 (dd,
1H, J = 13.7, and 3.7), 3.64–3.71 (m, 1H), 3.91–3.97 (m, 1H),
7.14–7.26 (m, 5H); 13C NMR (CD3OD) d 28.7, 37.7, 40.4, 58.0,
72.1, 79.9, 127.0, 129.1, 130.4, 140.2, 158.0, 176.3; IR (KBr)
3356, 2980, 1725, 1687.; HRMS(CI) calcd for C16H24NO5 (M++H)
310.1654, found 310.1654.
Acknowledgements
This research was supported by a grant from the Fundamental
R&D Program for Core Technology of Materials funded by the Min-
istry of Knowledge Economy, Republic of Korea. We would also like
to thank the BK-21 Program, Research Center for Energy Conver-
sion and Storage, Agency for Defense Development, SK Chemicals,
and Samsung Electronics for financial support.

1704
D. Yoo et al. / Tetrahedron: Asymmetry 22 (2011) 1700–1704
Larchevêque, M. Synlett 1999, 1118–1120; (d) Pais, G. C. G.; Maier, M. E. J. Org.
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