A new synthetic route to (3R,4S)-3-hydroxy-4-phenylazetidin-2-one as a taxol side chain precursor

Article abstract of DOI:10.1016/S0957-4166(98)00049-4

A new synthetic route to (3R,4S)-3-hydroxy-4-phenylazetidin-2-one, an important precursor for the paclitaxel side chain, has been developed using intramolecular cyclization of N-(p-methoxyphenyl) (2S,3R)-2-acetoxy-3-bromo- 3-phenylpropionamide which can be easily obtained by catalytic asymmetric dihydroxylation of N-(p-methoxyphenyl)-trans-cinnamide, followed by bromoacetylation.

Full text of DOI:10.1016/S0957-4166(98)00049-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 983–992
A new synthetic route to (3R,4S)-3-hydroxy-4-phenylazetidin-
2-one as a taxol side chain precursor
Choong Eui Song,a,∗ Sung Woo Lee,a Eun Joo Roh,a Sang-gi Lee a and Won-Ku Lee b
aDivision of Applied Science, Korea Institute of Science and Technology, PO Box 131, Cheongryang 130-650, Seoul,
South Korea
bDepartment of Chemistry, Sogang University, Seoul 121-742, South Korea
Received 12 January 1998; accepted 30 January 1998
Abstract
A new synthetic route to (3R,4S)-3-hydroxy-4-phenylazetidin-2-one, an important precursor for the paclitaxel
side chain, has been developed using intramolecular cyclization of N-(p-methoxyphenyl) (2S,3R)-2-acetoxy-3-
bromo-3-phenylpropionamide which can be easily obtained by catalytic asymmetric dihydroxylation of N-(p-
methoxyphenyl)-trans-cinnamide,followed by bromoacetylation. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Paclitaxel (taxol, 1), isolated from the bark of the Pacific Yew (Taxus brevifolia), is currently regarded
as one of the most promising new drugs in cancer chemotheraphy and has recently been approved for
treatment of metastatic ovarian and breast cancer.1 Other researchers have revealed its effects against non-
small cell lung cancer, head and neck cancer, glioblastoma and oesophageal cancer. In spite of attracting
worldwide attention as a most promising anticancer chemotherapeutic drug, very low isolation yields
(40–165 mg/kg of bark) of 1 from the stem bark of the yew tree leads to a supply problem. Fortunately,
it has been found that 10-deacetyl baccatin-III 2, possessing a very closely related structure to that of
paclitaxel, can be readily extracted from the leaves of the European Yew (Taxus baccata) in high yield
(ca. 1 g/kg of fresh leaves). It is important to recognize that the leaves are quickly regenerated and hence,
through prudent harvesting, a large amount of 10-deacetyl baccatin-III 2 can be supplied continuously
without threatening the survival of the yew species. From this renewable material, paclitaxel 1 could be
obtained by partial synthesis, and the problem of supply could be solved. It should also be noted that
10-deacetyl baccatin-III is at least 1000 times less active than paclitaxel and only paclitaxel with C-13
side chain having (2R,3S)-configuration, N-benzoyl-(2R,3S)-3-phenylisoserine 3, is active, which clearly
∗
Corresponding author. E-mail: s1673@kistmail.kist.re.kr
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00049-4

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demonstrates the importance of this C-13 side chain for anticancer activity. Therefore, the development of
short and practical synthetic routes to the enantiomerically pure phenylisoserine 3, which are adaptable
for industrial scale production, has become very important. Thus, much effort has been made in the
preparation of enantiomerically enriched phenylisoserine derivatives — semi-synthesis drawing from the
chiral pool,2 enzymatic and/or microbial processes,3 diastereoselective reactions with a covalently-bound
chiral auxiliary or with chiral substrates,4 asymmetric catalysis,5 and chemical resolution of racemic
acids.6
Greene et al.7a,b first reported a partial synthesis of paclitaxel, which involves the coupling of (2R,3S)-
N-benzoyl-O-(1-ethoxyethyl)-3-phenylisoserine with suitably protected baccatin-III in the presence of
an excess of DCC and DMAP in toluene at 75°C to give the corresponding ester. Unfortunately, under
the above mentioned reaction conditions, the 20-stereogenic center was easily epimerized. In order
to prevent the epimerization at 20-carbon, other coupling procedures have been developed.8 Among
these, especially, in the patent literature, Holton8a,b reported a new efficient coupling method using
suitably protected optically active β-lactam 4b as a side chain precursor, which allows no epimerization.
Therefore, the development of enantioselective synthetic routes, adaptable for industrial scale production,
to (3R,4S)-3-hydroxy-4-phenylazetidin-2-one 4a, a key intermediate for 4b, may be very important.
The typical procedures for obtaining enantiomerically pure β-lactam 4a involve 2,2-cycloaddition of
an extremely moisture sensitive chiral ester enolate and N-trimethylsilyl benzaldimine.8c–f However,
due to the sensitive reaction conditions and expensive chiral auxiliaries, these cycloaddition approaches
are not practical for commercial production of 4a. Now we have developed a new and more practi-
cal approach to the synthesis of optically active β-lactam 4a using the intramolecular cyclization of
β-bromocarboxamides which could be prepared starting from trans-cinnamide derivatives via catalytic
asymmetric dihydroxylation (AD), followed by bromoacetylation (Scheme 1). The results are described
in this paper.
Scheme 1.

C. E. Song et al. / Tetrahedron: Asymmetry 9 (1998) 983–992
985
2. Results and discussion
Our synthetic approach to (3R,4S)-3-hydroxy-4-phenylazetidin-2-one 4a outlined in Scheme 1 begins
with readily available trans-cinnamide derivatives.
2.1. AD reactions of trans-cinnamide derivatives 5a–d
Firstly, trans-cinnamide derivatives 5a–d were subjected to the K3Fe(CN)6-based catalytic AD
process9 using hydroquinine 1,4-phthalazinediyl diether ((DHQ)2PHAL) as a chiral ligand. The diol-
amides 6b,c were obtained in high chemical yields and high ee’s. In HPLC analyses (Chiralcel-AD, i-
PrOH:hexane=1:9), the ee’s of 6b,c were shown to be 96% and 94%, respectively. However, the AD
of the unsubstituted cinnamide 5a afforded 6a in only 48% yield. The diolamide 6a could be obtained
more efficiently by the reaction of enantiomerically enriched diol ester 7 with ammonia in ethanol at
room temperature (>99% yield). Interestingly, the AD reaction of amide 5d did not give the desired
diol product, instead only 8 could be isolated. The formation of 8 from 5d implies that under the
dihydroxylation conditions of amide 5d, the intramolecular benzoyl migration had arisen from amide
nitrogen to oxygen at the 2-position of the initially formed diol or its osmate ester (Scheme 2).
Scheme 2.
2.2. Bromoacetylation of diolamides 6a–c
As the second step, the diol amides 6a–c were efficiently converted to the acetoxy bromo amides
9a–c by reaction with trimethyl orthoacetate in the presence of catalytic amounts of p-TsOH at room
temperature (1 h), followed by treatment with acetyl bromide at −15°C (3 h) (Scheme 3).10 The products
can be easily purified by simple recrystallization from Et2O or benzene/hexane.

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Scheme 3.
2.3. Intramolecular cyclization of β-bromocarboxamides 9a–c
The treatment of the 2-acetoxy-3-bromocarboxamides 9b,c with tetrabutylammonium fluoride (TBAF)
in THF at room temperature gave the desired azetidinone 10b,c almost quantitatively.11 However, the
same reaction with 9a did not afford the desired azetidinone 10a, instead only iminoxetane 11 was
obtained (Scheme 4). The structure of 11 was assigned on the basis of the spectroscopic data. The
IR spectrum showed an intensive absorption at 1715 cm−1, attributed to the exocyclic imino function
(O–C_NH). In the case of 10b,c, the IR spectra showed an intensive absorption in the 1750–1760 cm−1
region, attributed to the exocyclic carbonyl function (O_C–N). Furthermore, the mass spectrum of 11
revealed, besides the molecular ion peak (m/z 205), a characteristic fragment pattern of 11, i.e. the ketene
imine (AcOCH_C_NH; m/z 99) and benzaldehyde (m/z 106) which can only be obtained from the
oxetane structure of 11 via retrocycloaddition along one of the two main axes of the ring.
Scheme 4.
The intramolecular cyclization of the β-halocarboxamides in the presence of base can involve nucleo-
philic substitution of halide by either the N or the O atom, which generally depends on the base and
the solvent. Generally, N-substitution predominates with strong bases in polar solvents, whereas with
weak bases in non polar solvents the products of O-substitution are normally observed.12 Thus, to find
appropriate reaction conditions favoring the formation of the wanted β-lactam 10a from 9a, the reactions
were carried out with strong bases in polar solvents (NaH in THF, NaH in DMF, NaH in DMSO, KH in
DMF, n-BuLi in THF etc.). However, all reactions examined by us so far gave only iminooxetane 11.

C. E. Song et al. / Tetrahedron: Asymmetry 9 (1998) 983–992
987
As a final step, the oxidative cleavage of the N-PMP group of 10c using ceric ammonium nitrate (CAN)
in aqueous CH3CN at 0°C gave (3R,4S)-3-acetoxy-4-phenylazetidin-2-one 10a in 80% yield. Hydrolysis
of 10a afforded the desired azetidinone 4a in 82%. However, the reductive debenzylation of 10b was not
successful in various conditions. The reaction of 10b in dissolving metals (Li/NH3) cleaved the N–C4
bond to give N-benzyl-3-phenylpropionamide (Scheme 5). It is well known that the reductive N–C4 bond
cleavage in 4-arylazetidin-2-one proceeds exclusively in a palladium catalyzed hydrogenolysis and thus
the benzyl–nitrogen bond remains intact.13
Scheme 5.
In conclusion, optically active β-lactam 4a was successfully prepared by intramolecular cyclization of
(2S,3R)-N-(p-methoxyphenyl)-2-acetoxy-3-bromo-3-phenylpropionamide 9c which could be easily ob-
tained starting from N-(p-methoxyphenyl)-trans-cinnamide 5c via catalytic asymmetric dihydroxylation
and bromoacetylation (5 steps, 51% overall yield). The present method provides a practical access to
enantiopure 4-hydroxyazetidinone 4a. Furthermore, all reactions proceed under mild reaction conditions
and all intermediates can be easily purified by simple recrystallization, which makes scale-up feasible.
3. Experimental section
3.1. General
Chromatographic purification of products was carried out by flash chromatography using Merck silica
gel 60 (230–400 mesh). Thin layer chromatography was carried out on Merck silica gel 60F plates.
Melting points were measured with a Thomas Hoover capillary melting point apparatus and were
1
uncorrected. Optical rotation was measured on a AUTOPOL III polarimeter (Rudolph Research). H
NMR (300 MHz) and 13C NMR (75.0 Hz) spectra were recorded on a Varian Gemini 300 spectrometer
using TMS as an internal standard. IR spectra were recorded on a MIDAC 101025 FT-IR spectrometer
and main absorption frequencies were given in cm−1. Elemental analyses were performed at the
Advanced Analytical Research Center in KIST using a Perkin–Elmer 240 C elemental analyzer.
3.2. (2R,3S)-2,3-Dihydroxy-3-phenylpropionamide (6a)
Method 1: (2R,3S)-Methyl-2,3-dihydroxy-3-phenylpropionate (7) (2.0 g, 10.2 mmol, [α]D=+10.1 (c
1.02, CHCl3), 94% ee) in MeOH was stirred at room temperature by passing NH3 gas through the mixture
until the reaction was completed. The solvent was evaporated, and the residue was simply purified by
stirring in CH2Cl2 to give 6a as a white solid (1.85 g, 99%, [α]D=+71.4 (c 1.02, H2O)).

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C. E. Song et al. / Tetrahedron: Asymmetry 9 (1998) 983–992
Method 2: To a well-stirred mixture of (DHQ)2PHAL (0.264 g, 0.34 mmol), K3Fe(CN)6 (6.71 g, 20.4
mmol), K2CO3 (2.82 g, 20.4 mmol) and CH3SO2NH2 (0.65 g, 6.8 mmol) in t-BuOH and H2O (1/1, v/v,
30 mL) was added 1% aqueous solution of OsO4 (0.0346 g, 0.136 mmol, 3.46 mL) at 0°C. After stirring
for 1 h, the amide 5a (1.0 g, 6.8 mmol) was added and stirring was continued at 0°C. When the reaction
was complete (ca. 4 days), sodium metabisulfite (1.94 g, 10.2 mmol) was added and stirred for 2 h. The
reaction mixture was extracted with EtOAc and the aqueous layer was reextracted with n-BuOH. The
combined organic extracts were concentrated in vacuo. The residue was purified by stirring with EtOAc
to give 6a as a white solid (0.59 g, 48%, 95% ee). The % ee was determined by comparison of the [α]D
value with the same compound prepared by method 1: mp 157°C; [α]D=+72.2 (c 1.04, H2O); 1H NMR
(300 MHz, DMSO-d6) δ 7.51–7.32 (m, 7H), 5.43 (d, J=6.9 Hz, 1H), 5.25 (d, J=6.9 Hz, 1H), 5.01 (dd,
J=6.9, 2.4 Hz, 1H), 4.00 (dd, J=6.9, 2.4 Hz, 1H); 13C NMR (75.0 MHz, DMSO-d6) δ 178.7, 147.2,
131.6, 130.6, 79.6, 77.2; IR (KBr) 3445, 3375, 3306, 1694, 1660, 1611, 1133, 1053, 734, 709 cm−1
anal. calcd for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.7; H, 6.07; N, 7.59.
;
3.3. N-Benzyl (2R,3S)-2,3-dihydroxy-3-phenylpropionamide (6b)
To a well-stirred mixture of (DHQ)2PHAL (0.039 g, 0.050 mmol), K3Fe(CN)6 (1.95 g, 5.91 mmol),
K2CO3 (0.82 g, 5.91 mmol) and CH3SO2NH2 (0.19 g, 1.97 mmol) in t-BuOH and H2O (1/1, v/v, 15
mL) was added 1% aqueous solution of OsO4 (0.005 g, 0.020 mmol, 0.5 mL) at 0°C. After stirring
for 1 h, the amide 5b (0.467 g, 1.97 mmol) was added and stirring was continued at 0°C. When the
reaction was complete (18 h), sodium metabisulfite (0.56 g, 2.95 mmol) was added and stirred for
2 h. The reaction mixture was extracted with EtOAc. After evaporation, the residue was purified by
chromatography on silica gel (EtOAc:hexane=1:1) to give 6b as a white solid (0.47 g, 88%, 96% ee):
mp 106–107°C; [α]D=+78.0 (c 1.1, CHCl3); 1H NMR (300 MHz, DMSO-d6) δ 8.20 (t, J=6.1 Hz, 1H),
7.40–7.20 (m, 10H), 5.35 (d, J=6.90 Hz, 1H), 5.33 (d, J=6.90 Hz, 1H), 4.93 (dd, J=6.90, 3.0 Hz, 1H),
4.31 (d, J=6.1 Hz, 2H), 4.02 (dd, J=6.90, 3.0 Hz, 1H); 13C NMR (75.0 MHz, DMSO-d6) δ 176.2, 147.0,
143.4, 132.1, 131.6, 131.1, 130.6, 79.8, 77.4, 45.8; IR (KBr) 3394, 3110, 1650, 1544, 1122, 1050, 742,
708 cm−1; anal. calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C, 70.7; H, 6.33; N, 5.28;
determination of enantiomeric excess: Chiralcel AD, i-PrOH:hexane=1:9, flow rate 1.0 mL/min, 254 nm,
23.3 min (2S,3R), 25.3 min (2R,3S).
3.4. N-(p-Methoxyphenyl) (2R,3S)-2,3-dihydroxy-3-phenylpropionamide (6c)
To a well-stirred mixture of (DHQ)2PHAL (0.039 g, 0.05 mmol), K3Fe(CN)6 (1.95 g, 5.91 mmol),
K2CO3 (0.82 g, 5.91 mmol) and CH3SO2NH2 (0.19 g, 1.97 mmol) in t-BuOH and H2O (1/1, v/v, 15 mL)
was added 1% aqueous solution of OsO4 (0.005 g, 0.020 mmol, 0.5 mL) at 0°C. After stirring for 1 h,
the amide 5c (0.50 g, 1.97 mmol) was added and stirring was continued at 0°C. When the reaction was
complete (24 h), sodium metabisulfite (0.56 g, 2.95 mmol) was added and stirred for 2 h. The reaction
mixture was extracted with EtOAc. After evaporation, the residue was purified by recrystallization from
i-PrOH to give 6c as a white solid (0.50 g, 88%, 94% ee): mp 199–201°C; [α]D=+113.3 (c 0.13, MeOH);
1H NMR (300 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.58 (d, J=9.0 Hz, 2H), 7.43–7.19 (m, 5H), 6.87 (d,
J=9.0 Hz, 2H), 5.52 (d, J=6.5 Hz, 1H), 5.39 (d, J=6.5 Hz, 1H), 4.97 (dd, J=6.5, 2.8 Hz, 1H), 4.07 (dd,
J=6.5, 2.8 Hz, 1H), 3.72 (s, 3H); 13C NMR (75.0 MHz, DMSO-d6) δ 74.6, 159.3, 147.0, 135.7, 131.6,
130.7, 130.6, 125.0, 117.7, 80.3, 77.4, 59.1; IR (KBr) 3354, 3316, 1644, 1548, 1512, 1250, 1108, 1034,
824, 706 cm−1; anal. calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C, 66.6; H, 6.00; N, 4.95;

C. E. Song et al. / Tetrahedron: Asymmetry 9 (1998) 983–992
989
determination of enantiomeric excess: Chiralcel AD, i-PrOH:hexane=1:9, flow rate 1.0 mL/min, 254 nm,
56.6 min (2S,3R), 35.6 min (2R,3S).
3.5. (2R,3S)-2-Benzoyloxy-3-hydroxy-3-phenylpropionamide (8)
To a well-stirred mixture of (DHQ)2PHAL (0.039 g, 0.05 mmol), K3Fe(CN)6 (1.97 g, 5.97 mmol),
K2CO3 (0.83 g, 5.97 mmol) and CH3SO2NH2 (0.19 g, 1.99 mmol) in t-BuOH and H2O (1/1, v/v, 15
mL) was added 1% aqueous solution of OsO4 (0.005 g, 0.020 mmol, 0.5 mL) at rt. After stirring for 1
h, 5d (0.5 g, 1.99 mmol) was added and stirring was continued at 0°C. When the reaction was complete
(72 h), sodium metabisulfite (0.57 g, 2.98 mmol) was added and stirred for 2 h. The reaction mixture
was extracted with EtOAc. After evaporation, the residue was purified by column chromatography
(EtOAc:hexane=1:1) to give 8 as a white solid (0.24 g, 42%): mp 152–153°C; [α]D=−31.1 (c 0.10,
MeOH); 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, J=7.6 Hz, 2H), 7.70–7.20 (m, 8H), 6.22 (d, J=2.2
Hz, 1H), 5.84 (d, J=7.1 Hz, 1H), 4.20 (dd, J=7.1, 2.2 Hz, 1H); 13C NMR (75.0 MHz, DMSO-d6) δ 173.2,
165.0, 138.3, 133.6, 129.7, 129.5, 128.8, 128.6, 128.2, 127.9, 127.7, 126.7, 126.5, 76.7, 74.1; IR (KBr)
3422, 3196, 1704, 1666, 1280, 1112, 714 cm−1; anal. calcd for C16H15NO4: C, 67.36; H, 5.30; N, 4.91.
Found: C, 66.9; H, 5.34; N, 4.88.
3.6. (2S,3R)-2-Acetoxy-3-bromo-3-phenylpropionamide (9a)
A solution of the diol amide 6a (0.9 g, 4.97 mmol), p-TsOH (0.013 g, 0.075 mmol) and trimethyl
orthoacetate (1.51 g, 12.57 mmol, 1.61 mL) in CH2Cl2/CH3CN (v/v=1/1, 20 mL) was stirred at room
temperature for 1 h. The volatiles were removed under reduced pressure, and the residue was taken up
in CH3CN (20 mL). After cooling the solution to −15°C, CH3COBr (1.16 g, 9.44 mmol, 0.76 mL) was
added dropwise, and stirring was continued for 3 h at −15°C. The reaction mixture was poured into water
and extracted with EtOAc. The organic extracts were dried over MgSO4 and concentrated in vacuo. The
residue was purified by flash column chromatography (EtOAc:hexane=2:1) to give 9a as a white solid
(1.34 g, 94%): mp 106–107°C; [α]D=−100.0 (c 1.10, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.46–7.25
(m, 5H), 5.90 (br s, 2H), 5.74 (d, J=6.4 Hz, 1H), 5.45 (d, J=6.4 Hz, 1H), 2.13 (s, 3H); 13C NMR (75.0
MHz, CDCl3) δ 170.1, 170.0, 137.1, 129.6, 129.3, 129.1, 76.4, 50.6, 21.2; IR (KBr) 3455, 3306, 3176,
1766, 1666, 1217, 1107, 1083, 799, 709, 619, 529 cm−1; anal. calcd for C11H12BrNO3: C, 46.18; H,
4.23; N, 4.90. Found: C, 46.2; H, 4.18; N, 4.79.
3.7. N-Benzyl (2S,3R)-2-acetoxy-3-bromo-3-phenylpropionamide (9b)
Compound 9b was prepared from 6b as for 9a: 6b (0.80 g, 2.95 mmol), p-TsOH (0.038 g, 0.22 mmol),
trimethyl orthoacetate (0.90 g, 7.46 mmol, 0.96 mL) and CH3COBr (0.69 g, 1.90 mmol, 0.45 mL). The
crude product was purified by silica gel column chromatography (EtOAc:hexane=1:1) to give 9b as a
1
white solid (1.07 g, 96%): mp 96–97°C; [α]D=−62.7 (c 1.1, CHCl3); H NMR (300 MHz, CDCl3) δ
7.48–6.92 (m, 10H), 6.33 (br s, 1H), 5.82 (d, J=5.7 Hz, 1H), 5.54 (d, J=5.7 Hz, 1H), 4.34 (d of ABq,
J=15.0, 6.9 Hz, 1H and 15.0, 4.8 Hz, 1H), 2.13 (s, 3H); 13C NMR (75.0 MHz, CDCl3) δ 170.0, 166.9,
137.7, 137.3, 129.6, 129.5, 129.3, 129.2, 128.2, 128.1, 77.0, 51.2, 43.9, 21.3; IR (KBr) 3286, 1751, 1671,
1566, 1247, 709 cm−1; anal. calcd for C18H18BrNO3: C, 57.46; H, 4.82; N, 3.72. Found: C, 57.1; H, 4.94;
N, 3.70.

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C. E. Song et al. / Tetrahedron: Asymmetry 9 (1998) 983–992
3.8. N-(p-Methoxyphenyl) (2S,3R)-2-acetoxy-3-bromo-3-phenylpropionamide (9c)
Compound 9c was prepared from 6c as for 9a: 6c (5.0 g, 17.4 mmol), p-TsOH (0.045 g, 0.26 mmol),
trimethyl orthoacetate (5.29 g, 44.0 mmol, 5.62 mL) and CH3COBr (4.07 g, 33.1 mmol, 2.68 mL). The
crude product was purified by recrystallization from benzene:hexane (2:1) to give 9c as a white solid
(6.47 g, 95%): mp 148°C; [α]D=−18.3 (c 1.13, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.38–7.26 (m,
5H), 7.16 (d, J=8.7 Hz, 2H), 6.75 (d, J=8.7 Hz, 2H), 5.73 (d, J=6.6 Hz, 1H), 5.45 (d, J=6.6 Hz, 1H), 3.71
(s, 3H), 2.05 (s, 3H); 13C NMR (75.0 MHz, CDCl3) δ 170.1, 165.1, 158.0, 137.3, 129.7, 129.3, 129.2,
123.2, 114.9, 77.3, 56.1, 51.1, 21.3; IR (KBr) 3306, 1755, 1601, 1551, 1521, 1237 cm−1; anal. calcd for
C18H18BrNO4: C, 55.12; H, 4.63; N, 3.57. Found: C, 54.8; H, 4.73; N, 3.44.
3.9. (3R,4S)-N-Benzyl-3-acetoxy-4-phenylazetidin-2-one (10b)
To the solution of 9b (0.70 g, 1.86 mmol) in THF (15 mL), tetrabutylammonium fluoride (1.0 M
solution in THF, 7.44 mL) was added at room temperature. After stirring for 3 h, the reaction mixture
was poured into water and extracted with EtOAc. The organic extracts were dried over MgSO4 and
concentrated in vacuo. The residue was purified by column chromatography (EtOAc:hexane=1:1) to give
1
10b as a white solid (0.51 g, 93%): mp 74–75°C; [α]D=+3.2 (c 1.2, CH2Cl2); H NMR (300 MHz,
CDCl3) δ 7.37–7.15 (m, 10H), 5.79 (d, J=4.4 Hz, 1H), 4.77 (d, J=4.4 Hz, 1H), 4.42 (ABq, J=14.6 Hz,
2H), 1.68 (s, 3H); 13C NMR (75.0 MHz, CDCl3) δ 170.0, 162.0, 157.3, 133.0, 131.0, 129.5, 129.2, 128.6,
119.5, 115.1, 77.1, 62.1, 56.1, 20.5; IR (KBr) 3276, 1756, 1661, 1237, 1083, 734, 709 cm−1; HRMS (EI)
calcd for C16H15NO2 (M–CH3CO): 253.1103. Found: 253.1116.
3.10. (3R,4S)-N-(p-Methoxyphenyl)-3-acetoxy-4-phenylazetidin-2-one (10c)
Compound 10c was prepared from 9c as above for 10b: 9c (11.1 g, 28.3 mmol) and tetrabutylammo-
nium fluoride (1.0 M solution in THF, 113.2 mL). The crude product was purified by recrystallization
from methanol to give 10c as a white solid (7.82 g, 94%): mp 144–145°C; [α]D=+10.8 (c 0.74, CH2Cl2);
1H NMR (300 MHz, CDCl3) δ 7.35–7.26 (m, 7H), 6.81 (d, J=9.0 Hz, 2H), 5.94 (d, J=4.9 Hz, 1H), 5.34
(d, J=4.9 Hz, 1H), 3.75 (s, 3H), 1.68 (s, 3H); 13C NMR (75.0 MHz, CDCl3) δ 169.9, 162.0, 157.3, 133.0,
131.0, 129.5, 129.2, 128.6, 119.5, 115.1, 77.1, 62.1, 56.1, 20.5; IR (KBr) 1756, 1521, 1232, 1112 cm−1
HRMS (EI) calcd for C16H15NO3 (M–CH3CO): 269.1052. Found: 269.1054.
;
3.11. 2-Imino-(3S,4S)-3-acetoxy-4-phenyloxetane (11)
A solution of 9a (0.5 g, 1.75 mmol) in THF (20 mL) was treated with tetrabutylammonium fluoride
(1.0 M solution in THF, 7.0 mL) at room temperature for 3 h under a nitrogen atmosphere. The
reaction mixture was poured into water and extracted with EtOAc. The organic extracts were dried
over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography
(EtOAc:hexane=2:1) to give 11 as a white solid (0.32 g, 89%): mp 86–87°C; [α]D=−90.9 (c 0.25,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 8.42 (br s, 1H), 7.40–7.27 (m, 5H), 4.00 (d, J=1.9 Hz, 1H),
3.61 (d, J=1.9 Hz, 1H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.5, 167.3, 136.7, 129.1, 128.63,
128.57, 75.2, 52.7, 49.1, 20.4; IR (KBr) 3345, 1740, 1715, 1511, 1207, 759, 704 cm−1; MS (EI) m/z
(relative abundance) 205 (1), 162 (2), 120 (31), 106 (39), 99 (100); anal. calcd for C11H11NO3: C, 64.38;
H, 5.40; N, 6.83. Found: C, 63.2; H, 5.45; N, 6.59.

C. E. Song et al. / Tetrahedron: Asymmetry 9 (1998) 983–992
991
3.12. (3R,4S)-3-Acetoxy-4-phenylazetidin-2-one (10a)
To the solution of 10c (2.1 g, 6.74 mmol) in CH3CN (60 mL) was added slowly a solution of
(NH4)2Ce(NO3)6 (11.08 g, 20.24 mmol) in water (90 mL) at 0°C. The mixture was stirred at 0°C for
1 h and diluted with water (150 mL). The mixture was then extracted with EtOAc. The organic extracts
were neutralized with 5% sodium bicarbonate and the aqueous extracts were washed with EtOAc. The
combined organic extracts were washed with 10% sodium sulfite, 5% sodium bicarbonate, and brine,
successively. The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was
purified by chromatography on silica gel (EtOAc:hexane=2:1) to give 4c as a white solid (1.10 g, 80%):
mp 181°C; [α]D=−15.7 (c 1.04, MeOH); 1H NMR (300 MHz, CDCl3) δ 7.65 (br s, 1H), 7.40–7.20 (m,
5H), 5.84 (d, J=4.6 Hz, 1H), 4.99 (d, J=4.6 Hz, 1H), 1.66 (s, 3H); 13C NMR (75.0 MHz, CDCl3) δ
169.6, 166.2, 135.5, 128.8, 128.0, 78.7, 58.1, 20.3; IR (KBr) 1760, 1730, 1237, 714 cm−1; anal. calcd
for C11H11NO3: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.4; H, 5.41; N, 6.53.
3.13. (3R,4S)-3-Hydroxy-4-phenylazetidin-2-one (4a)
To the solution of 10a (0.7 g, 3.41 mmol) in MeOH (5 mL), saturated NaHCO3 (7.0 mL) and Na2CO3
(0.036 g, 0.34 mmol) were added at room temperature. After the disappearance of the starting material,
the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified
by column chromatography (EtOAc:hexane=2:1) to give 4a as a white solid (0.46 g, 82%): mp 187°C;
[α]D=+182 (c 1.04, MeOH); 1H NMR (300 MHz, DMSO-d6) δ 8.47 (bs, 1H), 7.35–7.20 (m, 5H), 5.82
(d, J=6.8 Hz, 1H), 4.95 (dd, J=6.8, 4.5 Hz, 1H), 4.70 (d, J=4.5 Hz, 1H).
Acknowledgements
This work was supported by a grant from Ministry of Science and Technology in Korea. The authors
also thank Dr. Chong-Gi Hong for HRMS analyses of 10b,c.
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