Asymmetric synthesis of 3-amino-2-hydroxy-4-phenylbutanoate

Article abstract of DOI:10.1016/S0957-4166(99)00249-9

Asymmetric synthesis of 3-amino-2-hydroxy-4-phenylbutanoate, a key component of the natural product bestatin and HIV protease inhibitors of KNI- 272 and R-87366, has been achieved from the stereoselective aldimine coupling reaction between 3-phenyl-2-aminopropanenitrile and (Z)-α-methoxy trimethylsilyl ketene acetal in the presence of Lewis acids.

Full text of DOI:10.1016/S0957-4166(99)00249-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2327–2336
Asymmetric synthesis of 3-amino-2-hydroxy-4-phenylbutanoate†
Hyun-Joon Ha,a,∗ Young-Gil Ahn a and Gwan Sun Lee b
aDepartment of Chemistry, Hankuk University of Foreign Studies, Yongin, Kyunggi-Do 449-791, South Korea
bCentral Research Institute, Hanmi Pharmaceutical Co. Ltd., 371 Sampyung-dong, Seongnam, Kyunggi-Do 463-400,
South Korea
Received 6 May 1999; accepted 11 June 1999
Abstract
Asymmetric synthesis of 3-amino-2-hydroxy-4-phenylbutanoate, a key component of the natural product bes-
tatin and HIV protease inhibitors of KNI-272 and R-87366, has been achieved from the stereoselective aldimine
coupling reaction between 3-phenyl-2-aminopropanenitrile and (Z)-α-methoxy trimethylsilyl ketene acetal in the
presence of Lewis acids. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Bestatin is a dipeptide isolated from the culture filtrate of Streptomyces olivoreticuli with antitumor and
antibacterial activities.1 It is also known as a potent inhibitor of aminopeptidase B and of metalloenzyme
leukotriene A4 hydrolase.2 This dipeptide consists of the amino acid (S)-leucine and (2S,3R)-3-amino-2-
hydroxy-4-phenylbutanoic acid 1 as the key component. Its diastereomer 2 with the (2S,3S)-configuration
is also an important structural element of HIV-1 protease inhibitors represented by KNI 272 and R-
87366.3 Therefore, the stereoselective synthesis of 3-amino-2-hydroxy-4-phenylbutanoate has attracted
a great deal of attention over recent years.
Most approaches toward the enantioselective synthesis of 3-amino-2-hydroxy-4-phenylbutanoate came
from the chiral starting substrates such as phenylalanine,4 sugars, or their derivatives.5 Asymmetric
syntheses were also reported based on the methods including stereoselective reduction, epoxidation,
conjugate addition of amines, [2+2] cycloaddition of imines and ketene acetals, and aldol condensation
of chiral enolates and aldehydes.6From the viewpoint of our recent success in the synthesis of N-benzoyl-
(2R,3S)-phenylisoserine as the Taxol side chain, aldol type condensation of an imine with a ketene acetal
may give easy access to the enantioselective synthesis of 3-amino-2-hydroxy-4-phenylbutanoic acid.7
∗
†
Corresponding author. Fax: (+82)-335-3331696; e-mail: hjha@maincc.hufs.ac.kr
This paper is part 12 in the series of ‘Lewis acid induced synthetic equivalents of imines and iminum ion’. For Part 11, see:
Ha, H.-J.; Suh, J.-M.; Ahn, Y.-G; Dong, Y.; Yoon, H. Heterocycles 1999, 50, 203.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00249-9

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However, this method has not been reported to date because the corresponding imine phenylacetaldimine
is not available due to possible conversion of the imine to eneamine 2-phenyletheneamine.8 In this report
the first practical aldimine route to the stereoselective synthesis of 3-amino-2-hydroxy-4-phenylbutanoate
involving generation in situ of phenylacetaldimine equivalent and its coupling with ketene acetal is
described.
2. Results and discussion
2-Benzylamino-3-phenylpropanenitrile 3 was used as a precursor of a phenylacetaldiminium ion based
on the early observation9 that the nitrile at the α-position of an amine could be easily removed with
the assistance of Lewis acid. Initially, the crucial aldimine coupling reaction was studied between
2-benzylamino-3-phenylpropanenitrile 3 and the readily available nucleophile (Z)-1,2-dimethoxy-1-
trimethylsilyloxyethene 5,10 in the presence of several different Lewis acids as shown in Scheme 1 and
Table 1.
Scheme 1.
First MgBr2, a good catalyst for the coupling between N-benzylbenzaldimine and the same nucleophile
during the course of Taxol side chain synthesis, was tested.7 The result was not satisfactory though the
syn and anti stereoselectivities were as high as 78:22 at −15°C (entries 1–3). TiCl4, SnCl4, AlCl3 and

H.-J. Ha et al. / Tetrahedron: Asymmetry 10 (1999) 2327–2336
2329
Table 1
Reaction of 2-benzylamino-3-phenylpropanenitrile 3 and (Z)-1,2-dimethoxy-1-trimethylsilyloxy-
ethene 5 in the presence of Lewis acids
Sc(OTf)3 were no good either for obtaining more than 40% yield (entries 4–7). All reactions proceeded
in the syn fashion with ratios of 2:1–3:1. Other Lewis acids such as BF3·OEt2, TiF4 and Ti(OiPr)4 did not
lead to any detectable amounts of the product; instead all starting substrates remained unreacted. The best
result was obtained from the reaction with 1 mol equiv. of TMSOTf in 87% yield with the product with
the desired stereochemistry being major with the syn 7a to anti 7b ratio of 78:22 at room temperature for
2 h (entry 8). The stereochemical outcome and the reaction yield were not changed much with catalytic
amounts of Lewis acid or by lowering the reaction temperature (entries 9–11). Upon treatment of 2-
1
benzylamino-3-phenylpropanenitrile 3 with 10 mol% of TMSOTf new peaks were observed in the H
and 13C NMR at δ 5.45 and 167.8 ppm corresponding to the iminium ions with the removal of nitrile.
Thereafter, the reaction was performed at room temperature with 10 mol% of TMSOTf. The same
reaction with (Z)-1-t-butoxy-2-methoxy-1-trimethylsilyloxyethene 6 as a nucleophile was expected to
yield the product of t-butylester with better diastereoselectivity. However, the reaction did not proceed at
all due to possible steric hindrance in the approach to the iminium ion.
Once the reaction conditions were established, we carried out the reaction with the chiral substrate of
3-phenyl-2-[(R)-1-phenylethylamino]propanenitrile 4 considering the additional factor of diastereofacial
selectivity. From the standard Strecker synthesis from phenylacetaldehyde and (R)-1-phenylethylamine
was obtained 3-phenyl-2-[(R)-1-phenylethylamino]propanenitrile as a diastereomeric mixture of 2R and
2S with 4:1 ratio.11 This diastereomeric mixture was used for the next coupling reaction without further
purification or isolation because each isolated isomer yielded the same stereochemical outcome, possibly
due to the same iminium ion intermediate. With 10 mol% of TMSOTf, the aldimine coupling yielded
the expected product of methyl (2S,3R)-2-methoxy-4-phenyl-3-[(R)-1-phenylethylamino]butanoate 8a
as a major product among all four possible stereoisomers 8 in 59% isolated yield after flash column
chromatography (syn:anti=79:21, diastereofacial ratio=84:16). The transition state of the reaction can be
drawn, as shown in Scheme 2, with synclinal orientation of iminium ion activated by Lewis acid and
ketene acetal approaching the less hindered face of the chiral iminium ion.12
The coupled product (2S,3R)-2-methoxy-4-phenyl-3-[(R)-1-phenylethylamino]butanoate 8a was de-

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H.-J. Ha et al. / Tetrahedron: Asymmetry 10 (1999) 2327–2336
Scheme 2.
methylated with 0.3 mol equiv. of BBr3 at −78°C to give free hydroxy compound 9 with the minor
product of (3S,4R)-4-benzyl-3-methoxy-1-[(R)-1-phenylethyl]azetidin-2-one 11 in 81 and 16% isolated
yields, respectively (Scheme 3). The minor product 11 was also obtained from lactamization of 8a
with LHMDS in THF in quantitative yield. Hydrogenolysis of 9 afforded methyl (2S,3R)-3-amino-
2-hydroxy-4-phenylbutanoate 12 in 79% yield. Treatment of (2S,3R)-2-methoxy-4-phenyl-3-[(R)-1-
phenylethylamino]butanoate 8a with 1.0 mol equiv. of BBr3 at 0°C gave (3S,4R)-4-benzyl-3-hydroxy-1-
[(R)-1-phenylethyl]azetidin-2-one 10 which could be obtained as a crystalline solid after recrystallization
in diethyl ether.
Scheme 3.
Once the reaction sequence had been established, we succeeded in getting 10 in enantiomerically pure
form in 42% yield after two recrystallizations starting from a mixture of four stereoisomers 8 without
chromatographic separation of the single isomer 8a as shown in Scheme 4.
Scheme 4.
This afforded a practical route for getting a single enantiomerically pure 4-benzyl-3-hydroxyazetidin-
2-one from chiral amine, aldehyde and subsequent aldimine coupling with ketene acetal without any
tedious separation of diastereomers. Methanolysis and hydrogenolysis of azetidin-2-one 10 gave methyl
(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoate 12 {[α]D22=+19.4 (c 0.19, 1N HCl); lit.4c [α]D24=+19.6
(c 0.84, 1N HCl)} in 61% yield. Free acid 1 {[α]D24=+27.4 (c 0.43, 1N HCl)} was obtained by the
known method of hydrolysis in 2N HCl.13 Bestatin was readily prepared by coupling with (S)-leucine
tert-butylester by the reported method.4c This reaction sequence was applied successfully to prepare
several grams of (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoic acid 1 in good yield.

H.-J. Ha et al. / Tetrahedron: Asymmetry 10 (1999) 2327–2336
2331
Preparation of its diastereomer (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid 2 was achieved
as outlined in Scheme 5 utilizing the chiral amine (S)-1-phenylethylamine. The sequential
reactions of aldimine coupling, demethylation and lactamization starting from 3-phenyl-2-[(S)-1-
phenylethylamino]propanenitrile ent-4 with (Z)-α-methoxy trimethylsilyl ketene acetal afforded
(3R,4S)-4-benzyl-3-hydroxy-1-[(S)-1-phenylethyl]azetidin-2-one ent-10 that is also a synthetic precursor
of hydroxyethylene dipeptide isosteres.14 The subsequent methanolysis of ent-10 afforded (2R,3S)-2-
hydroxy-4-phenyl-3-[(S)-1-phenylethylamino]butanoate (ent-9). Hydrogenation and benzoylation of
ent-9 yielded the amide 13.
Scheme 5.
The same amide 13 was obtained from ent-8a separated from the diastereomeric mixture of the
initially coupled products as shown in Scheme 6. Hydrogenation and benzoylation of ent-8a afforded
methyl (2R,3S)-3-benzoylamino-2-methoxy-4-phenylbutanoate 14 which was readily converted to 13 by
demethylation with BBr3 in 90 and 79% yields, respectively. The target molecule (2S,3S)-3-amino-2-
hydroxy-4-phenylbutanoic acid 2 {[α]D22=−5.1 (c 0.19, 1N HCl); lit.6c [α]D20=−5.4 (c 0.51, 1N HCl)}
was obtained from 13 by the known literature procedure,15 including cyclization to cis-oxazoline under
Mitsunobu conditions with complete inversion of configuration at the α-position followed by hydrolysis
in 6N HCl.
Scheme 6.
In conclusion, we have found that the reaction of chiral iminium ion generated in situ from 3-
phenyl-2-[(R)-1-phenylethylamino]propanenitrile 4 with (Z)-α-methoxy trimethylsilyl ketene acetal in
the presence of a catalytic amount of TMSOTf yielded (2S,3R)-2-methoxy-4-phenyl-3-[(R)-1-phenyl-
ethylamino]butanoate 8a as the major component amongst all four possible stereoisomers. Demethylation
and lactamization with BBr3 from the aldimine coupled products without isolation of the major isomer
were successfully achieved to afford (3S,4R)-4-benzyl-3-hydroxy-1-[(R)-1-phenylethyl]azetidin-2-one
10 in an enantiomerically pure form after recrystallization. The subsequent reactions of methanolysis,
hydrogenolysis, and hydrolysis gave methyl (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoate 1 as a key
component of bestatin. Starting from the chiral amine (S)-1-phenylethylamine as a chiral auxiliary could
afford (3R,4S)-4-benzyl-3-hydroxy-1-[(S)-1-phenylethyl]azetidin-2-one ent-10 which leads to the syn-
thetically valuable (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid 2 by sequential transformations
including inversion of the configuration at the α-position.

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3. Experimental
3.1. General data
1
1H NMR and 13C NMR spectra were recorded on a Varian 200 or 400 (200 and MHz for H and
50.3 and 100.6 MHz for 13C). Chemical shifts were given in ppm using TMS as internal standard.
Mass spectra were obtained using a Hewlett Packard Model 5985B spectrometer or a Kratos Concept
1-S double focusing mass spectrometer. Elemental analyses were taken on a Perkin–Elmer 240 DS
elemental analyzer. Melting points were measured by Mel-II capillary melting point apparatus. Optical
rotations were measured with a Rudolph Research Autopole 3 polarimeter. The silica gel used for column
chromatography was Merck 200–230 mesh. Thin layer chromatography was carried out with Merck 60F-
254 plates with 0.25 mm thickness.
3.2. 2-Benzylamino-3-phenylpropanenitrile 3
Phenylacetaldehyde (3.23 g, 26.8 mmol) and NaHSO3 (2.80 g, 26.9 mmol) were dissolved in H2O
(7 ml) and MeOH (22 ml). Into this was added benzylamine (3.71 g, 34.6 mmol) and KCN (2.25 g,
34.6 mmol). The resulting mixture was refluxed for 1 h for the completion and cooled down to room
temperature before quenching by addition of H2O (50 ml). The reaction product was extracted with
EtOAc (50 ml) three times. The extracts were washed by 100 ml each of water and brine, dried by
anhydrous MgSO4, filtered and concentrated under reduced pressure to give 6.20 g of the expected
1
product that was used without further purification. H NMR δ 1.58 (br s, 1H), 3.01 (d, 1H, J=5.4 Hz),
3.04 (d, 1H, J=4.2 Hz), 3.70 (t, 1H, J=6.1 Hz), 3.78 (d, 1H, J=13.2 Hz), 3.93 (d, 1H, J=13.2 Hz),
7.20–7.34 (m, 10H); 13C NMR δ 39.1, 50.6, 51.3, 119.5, 127.5, 128.2, 128.5, 128.7, 129.5, 135.0, 138.1.
3.3. 3-Phenyl-2-[(R)-1-phenylethylamino]propanenitrile 4
This was prepared in the same manner to make 2-benzylamino-3-phenylpropanenitrile (3) utilizing
(R)-phenylethylamine instead of benzylamine in 98% yield with the diastereomeric ratio of 4:1. Two dia-
stereomers were separated by flash column chromatography with hexane and EtOAc (3:1, v/v) as eluent.
However, for the next aldimine reaction the crude reaction product as a diastereomeric mixture was used
without any further purification or isolation. (2R)-3-Benzyl-2-[(R)-1-phenylethylamino]propanenitrile 4,
1H NMR δ 1.19 (d, 3H, J=6.4 Hz), 1.44 (br s, 1H), 2.82–2.86 (m, 2H), 3.29 (t, 1H, J=6.1 Hz), 3.91 (q,
1H, J=6.6 Hz), 7.04–7.24 (m, 10H); 13C NMR δ 24.6, 39.2, 49.1, 56.2, 119.7, 126.7, 127.3, 128.5, 128.6,
129.4, 135.1, 143.1. (2S)-3-Benzyl-2-[(R)-1-phenylethylamino]propanenitrile 4, 1H NMR δ 1.20 (d, 3H,
J=6.4 Hz), 1.47 (br s, 1H), 2.90–2.92 (m, 2H), 3.29 (t, 1H, J=6.1 Hz), 3.47 (q, 1H, J=5.8 Hz), 7.04–7.24
(m, 10H); 13C NMR δ 22.1, 39.2, 49.4, 55.8, 119.5, 126.6, 127.4, 128.6, 128.9, 129.2, 135.1, 144.4.
3.4. Methyl 3-benzylamino-2-methoxy-4-phenylbutanoate 7
Lewis acid TMSOTf (0.18 ml, 222 mg, 1 mmol) was added to the solution of 2-benzylamino-3-
phenylpropanenitrile 3 (2.36 g, 10 mmol) in CH2Cl2 at room temperature. The resultant solution was
stirred for 15 min before adding (Z)-1,2-dimethoxy-1-trimethylsilyloxyethene (1.76 g, 10 mmol) in
drops. After 1 h for completion the reaction mixture was dumped into the H2O. The reaction product was
extracted with EtOAc (50 mL) three times. The organic layer was washed by 100 ml each of water and
brine, dried by anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product

H.-J. Ha et al. / Tetrahedron: Asymmetry 10 (1999) 2327–2336
2333
was purified by flash column chromatography to give 2.81 g of analytically pure products 7a and 7b. For
1
7a: H NMR δ 2.68 (dd, 1H, J=13.0, 9.0 Hz), 2.95 (dd, 1H, J=13.0, 5.4 Hz), 3.05–3.12 (m, 1H), 3.33
(s, 3H), 3.47 (d, 1H, J=2.8 Hz), 3.56 (s, 3H), 3.67 (1H, d, J=13.4 Hz), 3.81 (d, 1H, J=13.4 Hz), 4.21 (br
s, 1H), 7.06–7.26 (m, 10H); 13C NMR δ 37.0, 51.0, 51.5, 58.7, 60.5, 80.9, 126.3, 127.0, 128.2, 128.3,
1
128.6, 129.3, 139.2, 140.5, 172.5. For 7b: H NMR δ 2.71–2.77 (m, 2H), 3.12–3.27 (m, 1H), 3.33 (s,
3H), 3.49 (d, 1H, J=19.4 Hz), 3.62 (s, 3H), 3.66 (d, 1H, J=19.4 Hz), 3.69 (d, 1H, J=2.0 Hz), 4.23 (br
s, 1H), 7.06–7.28 (m, 10H); 13C NMR δ 36.2, 51.4, 51.7, 58.7, 60.2, 81.9, 126.3, 126.9, 128.1, 128.3,
128.4, 129.6, 138.5, 140.2, 172.3.
3.5. Methyl (2S,3R)-2-methoxy-4-phenyl-3-[(R)-1-phenylethylamino]butanoate 8a
This title compound was prepared in the same manner to make methyl 3-benzylamino-2-methoxy-4-
phenylbutanoate 7 starting from 3-phenyl-2-[(R)-1-phenylethylamino]propanenitrile 4 (2.50 g, 10 mmol)
1
instead of 2-benzylamino-3-phenylpropanenitrile 3. H NMR δ 1.15 (d, 3H, J=6.6 Hz), 1.58 (s, 1H),
2.63 (d, 2H, J=7.6 Hz), 3.08 (t, d, 1H, J=7.2, 2.0 Hz), 3.29 (s, 3H), 3.39–3.47 (m, 1H), 3.60 (s, 3H),
3.69 (q, 1H, J=6.3 Hz), 6.94–7.19 (m, 10H); 13C NMR δ 23.9, 38.2, 51.2, 55.5, 58.4, 59.0, 80.2, 126.2,
126.4, 127.0, 128.2, 128.5, 129.2, 139.0, 145.7, 172.4. [α]D22=+39.3 (c 0.19, CH2Cl2). MS m/z: 327
(M, 2), 312 (10), 236 (31), 224 (23), 120 (30), 105 (100). Anal. calcd for C20H25NO3: C, 73.4; H,
7.70; N, 4.28. Found: C, 73.7; H, 7.45; N, 4.66. All other isomers were separated by flash column
chromatography. Their stereochemistry was identified based on the coupling constants between α- and
β-protons of β-lactams derived by the reaction with LHMDS as described in the part of compound
1
11. Methyl (2R,3R)-2-methoxy-4-phenyl-3-[(R)-1-phenylethylamino]butanoate: H NMR δ 1.21 (d, 3H,
J=6.6 Hz), 1.58 (br s, 1H), 2.61 (d, 2H, J=7.2 Hz), 2.67–2.84 (m, 1H), 3.32 (s, 3H), 3.66 (d, 1H, J=7.2
Hz), 3.46 (s, 3H), 3.88 (q, 1H, J=6.5 Hz), 6.96–7.21 (m, 10H); methyl (2S,3S)-2-methoxy-4-phenyl-3-
[(R)-1-phenylethylamino]butanoate: 1H NMR δ 1.23 (d, 3H, J=6.6 Hz), 1.55 (s, 1H), 2.63–2.67 (m, 2H),
3.02 (ddd, 1H, J=8.2, 5.6, 3.8), 3.45 (s, 3H), 3.69 (s, 3H), 3.69 (q, 1H, J=6.6 Hz), 3.89 (d, 1H, J=3.8
Hz), 6.93–7.25 (m, 10H); methyl (2R,3S)-2-methoxy-4-phenyl-3-[(R)-1-phenylethylamino]butanoate:
1H NMR δ 1.55 (d, 3H, J=6.6 Hz), 1.57 (s, 1H), 2.75 (d, 2H, J=6.0 Hz), 3.01 (q, 1H, J=5.8 Hz), 3.21 (s,
3H), 3.41 (d, 1H, J=5.6 Hz), 3.52 (s, 3H), 3.77 (q, 1H, J=6.4 Hz), 7.07–7.27 (m, 10H).
3.6. Methyl (2S,3R)-2-hydroxy-4-phenyl-3-[(R)-1-phenylethylamino]butanoate 9
BBr3 (7.72 mg, 3.1 mmol) was added to the solution of methyl (2S,3R)-2-methoxy-4-phenyl-3-[(R)-1-
phenylethylamino]butanoate 8a (335 mg, 1.03 mmol) in CH2Cl2 (30 ml) at −78°C. The resultant reaction
mixture was stirred for 2 h at −78°C before adding H2O (30 ml). The solution was neutralized with
2N NaOH solution. The reaction product was extracted with EtOAc (50 ml) three times. The extracts
were washed by 100 ml each of water and brine, dried by anhydrous MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by flash column chromatography to give 261
1
mg of the title compound as major fraction. H NMR δ 1.13 (d, 3H, J=6.6 Hz), 2.64–2.69 (m, 2H),
3.03–3.11 (m, 1H), 3.52 (q, 1H, J=6.5 Hz), 3.67 (s, 3H), 3.87 (d, 1H, J=1.6 Hz), 6.83–7.23 (m, 10H);
13C NMR δ 23.9, 39.0, 52.0, 55.6, 58.3, 70.7, 126.3, 126.5, 127.0, 128.4, 128.6, 129.4, 138.2, 145.1,
175.2. [α]D22=−13.3 (c 0.80, CH2Cl2). MS m/z: 295 (M−18, 2), 176 (2), 148 (100). Anal. calcd for
C19H23NO3: C, 72.8; H, 7.40; N, 4.47. Found: C, 72.6; H, 7.66; N, 4.38. (3S,4R)-4-Benzyl-3-methoxy-
1-[(R)-1-phenylethyl]azetidin-2-one (48 mg, 11) was also obtained as a minor product in 16% yield. 1H
NMR δ 1.52 (d, 3H, J=7.2 Hz), 2.71 (dd, 1H, J=14.4, 5.2 Hz), 2.91 (dd, 1H, J=14.4, 8.2 Hz), 3.31 (s, 3H),
3.68–3.78 (m, 1H), 4.28 (d, 1H, J=2.8 Hz), 4.47 (q, 1H, J=7.2 Hz), 6.92–7.30 (m, 10H); 13C NMR δ 19.7,

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35.2, 52.2, 59.2, 59.6, 83.4, 126.3, 127.0, 127.7, 128.3, 128.6, 129.0, 137.6, 140.0, 167.4. [α]D22=−43.4
(c 0.80, CH2Cl2). Anal. calcd for C19H21NO2: C, 77.3; H, 7.17; N, 4.74. Found: C, 77.4; H, 6.98;
N, 4.54. (3S,4R)-4-Benzyl-3-methoxy-1-[(R)-1-phenylethyl]azetidin-2-one 11 was also obtained in 97%
yield from the reaction of methyl (2S,3R)-2-methoxy-4-phenyl-3-[(R)-1-phenylethylamino]butanoate 8a.
Compound 8a (50 mg 153 mmol) was added to LHMDS (153 mmol) solution in THF (15 ml) at −78°C.
Then the cooling bath was removed and the resultant solution was stirred at 0°C for 2 h before adding the
water. The reaction product was extracted with EtOAc (50 ml) twice. The extracts were washed by 50 ml
each of water and brine, dried by anhydrous MgSO4, filtered and concentrated under reduced pressure.
The crude product was purified by flash column chromatography to give 147 mg of the lactamized
product 11.
3.7. (3S,4R)-4-Benzyl-3-hydroxy-1-[(R)-1-phenylethyl]azetidin-2-one 10
BBr3 (1.00 g, 4.0 mmol) was added at 0°C to the solution of the diastereomeric mixture of methyl
2-methoxy-4-phenyl-3-[(R)-1-phenylethylamino]butanoate 8 (1.31 g, 4.0 mmol) from the aldimine
coupling reaction without any purification in CH2Cl2. Then the resultant reaction mixture was stirred
for 10 h at room temperature before adding H2O (30 ml). The solution was neutralized with 2N NaOH
solution. The reaction product was extracted with EtOAc (50 ml) three times. The extracts were washed
by 100 ml each of water and brine, dried by anhydrous MgSO4, filtered and concentrated under reduced
pressure. The crude product was dissolved in a minimum amount of ethyl ether and recrystallized at 4°C
1
to give 517 mg of white crystalline solid in 46% overall yield. H NMR δ 1.54 (d, 3H, J=7.2 Hz), 2.73
(dd, 1H, J=5.1, 4.8 Hz), 3.08 (dd, 1H, J=14.0, 8.3 Hz), 3.67–3.76 (m, 1H), 4.64–4.77 (m, 2H), 5.15 (br
s, 1H), 6.99–7.31 (m, 10H); 13C NMR δ 19.8, 34.9, 52.5, 60.8, 75.3, 126.4, 127.1, 127.8, 128.4, 128.7,
129.2, 137.8, 139.8, 170.2. [α]D22=+52.1 (c 0.12, CH2Cl3). Anal. calcd for C18H19NO2: C, 76.8; H,
6.81; N, 4.98. Found: C, 76.5; H, 6.62; N, 4.81.
3.8. Methyl (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoate 12
In CH3OH (20 ml) were dissolved methyl (2S,3R)-2-hydroxy-4-phenyl-3-[(R)-1-phenylethyl-
amino]butanoate 9 (500 mg, 1.60 mmol) and Pd–C (30 mg). This solution was blanketed with H2 gas in
a balloon and the mixture was stirred at room temperature until all starting material was consumed on
TLC for 15 h. The mixture was filtered and concentrated under reduced pressure. This crude reaction
product was purified by flash column chromatography to give 264 mg of the title compound in 79%
yield. [α]D22=+19.4 (c 0.19, 1N HCl); lit,9a [α]D24=+19.6 (c 0.84, 1N HCl).
3.9. Methyl (2R,3S)-2-methoxy-4-phenyl-3-[(S)-1-phenylethylamino]butanoate ent-8a
This was prepared in the same manner as for 8a utilizing 3-phenyl-2-[(S)-1-phenylethylamino]propane-
nitrile ent-4 instead of 3-phenyl-2-[(R)-1-phenylethylamino]propanenitrile 4. [α]D22=−38.7 (c 0.24,
CH2Cl2).
3.10. (3R,4S)-4-Benzyl-3-hydroxy-1-[(S)-1-phenylethyl]azetidin-2-one ent-10
This was prepared in the same manner as for 10 starting from the diastereomeric mixture of methyl
2-methoxy-4-phenyl-3-[(S)-1-phenylethylamino]butanoate (ent-8). [α]D22=−53.1 (c 0.18, CH2Cl2).

H.-J. Ha et al. / Tetrahedron: Asymmetry 10 (1999) 2327–2336
2335
3.11. Methyl (2R,3S)-3-benzoylamino-2-hydroxy-4-phenylbutanoate 13
In CH3OH (20 ml) was dissolved Pd–C (50 mg) and compound ent-9 (190 mg, 0.61 mmol) that was
prepared from ent-10 by the same procedure for the molecule 10. This solution, blanketed with H2 gas
in a balloon, was stirred at room temperature until all starting material was consumed on TLC for 15
h. The mixture was filtered and concentrated under reduced pressure. This crude reaction product was
dissolved in a mixture of THF (5 mL) and water (5 mL). Benzoyl chloride (85 mg, 0.61 mmol) was added
dropwise to this solution at 0°C maintaining pH 9–10 with NaOH solution. After addition was completed
the resultant reaction mixture was stirred vigorously for 30 min. The reaction product was extracted with
EtOAc (50 ml) three times. The extracts were washed by 100 ml each of water and brine, dried by
anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by
1
flash column chromatography to give 150 mg of the title compound in 79% yield. Mp 102–104°C; H
NMR δ 2.91–2.99 (m, 2H), 3.61 (s, 3H), 4.13 (s, 1H), 4.67 (br s, 1H), 4.72 (q, 1H, J=7.4 Hz), 6.64 (d,
1H, J=9.2 Hz), 7.11–8.01 (m, 10H); 13C NMR δ 37.7, 52.9, 53.4, 70.1, 126.7, 126.9, 128.5, 128.6, 129.3,
131.6, 134.0, 137.2, 167.4, 174.1. [α]D22=−19.8 (c 0.30, CH2Cl2). Anal. calcd for C18H19NO4: C, 69.0;
H, 6.11; N, 4.47. Found: C, 69.2; H, 6.31; N, 4.68.
3.12. Methyl (2R,3S)-3-benzoylamino-2-methoxy-4-phenylbutanoate 14
The same reaction as in compound 13 from ent-9 was carried out with the starting material of ent-8a
(1.27 g, 3.88 mmol) to yield the expected product in 90% yield as a white solid. Mp 148–150°C; 1H NMR
δ 2.91 (dd, 1H, J=13.6, 8.8 Hz), 3.08 (dd, 1H, J=13.2, 6.2 Hz), 3.41 (s, 3H), 3.62 (s, 3H), 3.70 (d, 1H,
J=1.8 Hz), 4.78 (q, 1H, J=9.6 Hz), 6.65 (d, 1H, J=9.2 Hz), 7.17–7.74 (m, 10H); 13C NMR δ 37.5, 51.9,
53.0, 58.3, 78.3, 126.5, 126.8, 128.2, 128.5, 129.1, 131.3, 134.1, 137.2, 166.8, 171.0. [α]D22=−45.9 (c
0.21, CH2Cl2). Anal. calcd for C19H21NO4: C, 69.7; H, 6.47; N, 4.28. Found: C, 69.4; H, 6.61; N, 4.59.
3.13. Methyl (2R,3S)-3-benzoylamino-2-hydroxy-4-phenylbutanoate 13 from 14
BBr3 (152 mg, 0.61 mmol) was added into the solution of methyl (2R,3S)-3-benzoylamino-2-methoxy-
4-phenylbutanoate 14 (200 mg, 0.61 mmol) in CH2Cl2 (30 ml) at −78°C. After 10 min the cooling
bath was removed and the resultant reaction mixture was stirred for 2 h before adding H2O (30 ml).
The solution was neutralized with Na2CO3 solution. The reaction product was extracted with CH2Cl2
(30 ml) three times. The extracts were washed by 50 ml each of water and brine, dried by anhydrous
MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash
column chromatography to give 151 mg of the title compound 13.
3.14. (2S,3S)-3-Amino-2-hydroxy-4-phenylbutanoic acid 2
A solution of triphenylphosphine (289 mg) and diethyldiazodicarboxylate (191 mg, 1.10 mmol) in
THF (20 ml) was added dropwise to methyl (2R,3S)-3-benzoylamino-2-hydroxy-4-phenylbutanoate 13
(150 mg, 0.479 mmol) dissolved in 20 mL of THF at 0°C under a N2 atmosphere. The reaction mixture
was allowed to warm to room temperature and stirred at this temperature for 28 h. The solution was
concentrated under reduced pressure to give a brownish partial solid that was chromatographed by a
short-path flash column with n-hexane and EtOAc (3:1, v/v). A solution of this solid in 6N HCl (20
ml) was refluxed for 6 h. After the reaction was completed, the mixture was cooled down. This was
washed with 20 ml of diethyl ether. The aqueous layer was concentrated under reduced pressure. This

2336
H.-J. Ha et al. / Tetrahedron: Asymmetry 10 (1999) 2327–2336
was adsorbed on Dowax 50W (250 ml) column and eluted with 2N NH4OH to afford the product as a
white solid (54 mg). [α]D22=−5.1 (c 0.09, 1N HCl); lit.6c [α]D20=−5.4 (c 0.51, 1N HCl).
Acknowledgements
This work was supported by the Center for Biofunctional Molecules, Korea Science and Engineering
Foundation (97-0501-02-01-3) and the Ministry of Education (BSRI 98-3437).
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