Ephedrine derived reusable chiral auxiliary for the synthesis of optically pure 3-hydroxy-4-aryl-β-lactams

Article abstract of DOI:10.1016/S0957-4166(03)00039-9

The diastereoselective synthesis of various β-lactams has been achieved using a chiral acid auxiliary derived from (-)-ephedrine. An efficient acid-catalyzed cleavage of the chiral auxiliary from these β-lactams to afford 3-hydroxy-4-aryl-cis-β-lactams, which are precursors for analogues of the taxol side chain, is described.

Full text of DOI:10.1016/S0957-4166(03)00039-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 453–459
Ephedrine derived reusable chiral auxiliary for the synthesis of
optically pure 3-hydroxy-4-aryl-b-lactams
Bidhan A. Shinkre,a Vedavati G. Puranik,b B. M. Bhawalc and A. R. A. S. Deshmukha,*
aDivision of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
bDivision of Physical Chemistry, National Chemical Laboratory, Pune 411 008, India
cEmcure Pharmaceuticals Ltd., Emcure House, T-184, M. I. D. C., Bhosari, Pune 411026, India
Received 12 November 2002; accepted 8 January 2003
Abstract—The diastereoselective synthesis of various b-lactams has been achieved using a chiral acid auxiliary derived from
(−)-ephedrine. An efficient acid-catalyzed cleavage of the chiral auxiliary from these b-lactams to afford 3-hydroxy-4-aryl-cis-b-
lactams, which are precursors for analogues of the taxol side chain, is described. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
taxol side chain. However, the chiral auxiliary is either
unrecoverable or lost during the oxidative removal of
the auxiliary, thereby making this methodology less
attractive. We report herein a solution to this problem
by using a chiral auxiliary derived from the readily
available (−)-ephedrine, which can be removed under
mild conditions and recovered in quantitative yield
without racemization and is therefore readily recycled.
The b-lactam skeleton has gained significant interest
among synthetic as well as medicinal chemists over the
years, mainly because it represents the core structure of
synthetic and natural b-lactam antibiotics.1 The impor-
tance of the b-lactam unit as a synthon has been
recognized in the synthesis of a variety of biologically
important b-lactam and non-b-lactam derivatives.2 It
has been shown that a suitably substituted 3-hydroxy-
b-lactam can serve as a synthetic equivalent for the
phenylisoserine3 side chain of taxol, an anticancer agent
obtained from the bark of Taxus brevifolia or can be
directly coupled with baccatin III4 (a precursor of taxol
which is available in sufficient quantities from the
leaves of the plant) to give taxol. 3-Hydroxy-b-lactams
are also a source of enantiomerically pure a-hydroxy-b-
amino acids, which are present in many biologically
important compounds.5–7 The preparation of suitably
substituted (3R,4S)-3-hydroxy-b-lactams by diastereo-
selective cycloaddition reaction,3,4,8,9 borohydride
reduction of 3-ketoazetidinones10 and the resolution of
( )-3-hydroxy-b-lactams11 have been reported.
2. Results and discussion
The hemiketal 3 was easily prepared from (−)-ephedrine
1 and a-ketopropionoyl chloride.13 The absolute stereo-
chemistry of this hemiketal has been established previ-
ously.13 Alternatively the same hemiketal can also be
prepared by reacting (−)-ephedrine with oxalyl chloride
followed by addition of Grignard reagent to the corre-
sponding lactone 2.14 The resulting hemiketal 3 was
then alkylated with ethyl bromoacetate followed by
hydrolysis of the corresponding ester to afford the
chiral acid 4, which was characterized by its spectro-
scopic data (IR, NMR) (Scheme 1). Cycloaddition
reaction of acid 4 with various imines 5 in the presence
of triethylamine and triphosgene as an acid activator
furnished a diastereomeric mixture of cis-b-lactams 6
and 7) in good yields (Scheme 2, Table 1). The
diastereomers were easily separated by flash column
In continuation of our efforts into the synthesis of
homochiral b-lactams and their use as synthons,12 we
have recently reported the use of a chiral auxiliary
derived from the readily available and naturally abun-
dant (+)-3-carene12f,j in an asymmetric synthesis of the
chromatography.
The
stereochemistry
of
the
diastereomer 7b was confirmed by single crystal X-ray
diffraction15 and the stereochemistry was assigned as
3S,4R for the b-lactam ring (Fig. 1).
* Corresponding author. Fax: +91-20-5893153; e-mail: arasd@
dalton.ncl.res.in
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(03)00039-9

454
B. A. Shinkre et al. / Tetrahedron: Asymmetry 14 (2003) 453–459
Scheme 1.
Scheme 2.
Table 1. Synthesis of cis-b-lactams 6a–d and 7a–d from chiral acid 4 and imines 5a–d
Entry no.
Product
R1
R2
Yielda (%)
Diastereoselectivityb
1
2
3
4
6a and 7a
6b and 7b
6c and 7c
6d and 7d
Ph
PMP
Ph
PMP
Ph
70
60
65
65
50:50
60:40
65:35
56:44
PMP
PMP
Ph
a Isolated yields of diastereomeric mixture.
b Ratio determined from 1H NMR spectral analysis of crude reaction mixture
On heating under reflux with PTSA in aqueous THF
for about 10–12 h the pure diastereomers 6 and 7 gave
the corresponding enantiomerically pure 3-hydroxy-cis-
b-lactams 8a, 9a–d in near-quantitative yields (Scheme
3, Table 2) by column chromatography. The formation
of 3-hydroxy-b-lactams 8a and 9a–d was confirmed
from their spectroscopic data (IR, 1H NMR). The
absolute configuration of the b-lactams 8 and 9 was
assigned as 3R,4S and 3S,4R, respectively, by compar-
ing their physical data as well as their specific rotation

B. A. Shinkre et al. / Tetrahedron: Asymmetry 14 (2003) 453–459
455
Figure 1. ORTEP drawing of 7b.
Scheme 3.
Table 2. Synthesis of 3-hydroxy-cis-b-lactams 8a and 9a–d from enantiomerically pure diastereomers 6a and 7a–d
Entry no.
R1
R2
Product
Yield (%)a
Mp (°C)
[h]D (CHCl3)
Configuration
1
2
3
4
5
Ph
Ph
PMP
PMP
Ph
PMP
PMP
Ph
PMP
Ph
8a
9a
9b
9c
9d
90
90
85
88
84
196–197
201–202
212–213
132–133
216–217
+180.0 (c 0.40) lit.12j +176.0 (c 1.00)
−178.0 (c 0.90) lit.12j −179 (c 1.00)
−173.7 (c 1.00)
3R,4S
3S,4R
3S,4R
3S,4R
3S,4R
−179.1 (c 2.20) lit.12j −181.9 (c 0.93)
−188.4 (c 0.90) lit.12j −188.7 (c 0.39)
a Isolated yield of pure enantiomers.

456
B. A. Shinkre et al. / Tetrahedron: Asymmetry 14 (2003) 453–459
values with those of compounds 8a, 9a, 9c and 9d reported
59.8, 60.7, 71.2, 99.3, 125.5, 127.5, 128.2, 137.0, 165.8,
169.8; MS: m/z 321 (M+). Anal. calcd for C17H23NO5: C,
63.53; H, 7.21; N, 4.36. Found: C, 63.80; H, 7.50; N,
4.69%.
in the literature.12j
The hemiketal 3 formed during the hydrolysis of 6 and
7 was also isolated in quantitative yield by column
chromatography and characterized by IR and 1H NMR
spectroscopy. There was no loss in enantiomeric purity
of the recovered hemiketal 3 as it showed exactly the same
specific rotation value {[h]2D5 −107.6 (c 1.4, CHCl3)} as
that of the starting hemiketal.
4.3. Preparation of (2S,5S,6R)-[(2,4,6-trimethyl-3-oxo-
6-phenylmorpholin-2-yl)oxy]acetic acid, 4
To the solution of ester (963 mg, 3 mmol) in THF (9 mL)
was added aqueous NaOH (1 M, 9 mL) and stirred at
ambient temperature for 5–6 h. THF was removed under
reduced pressure. Aqueous layer was acidified with Conc.
HCl dropwise and extracted with ethyl acetate (3×15 mL).
The combined organic layers were washed with brine
solution (2×10 mL), dried over anhydrous Na2SO4 and
concentrated to give 4 as a white solid (800 mg, 91%);
mp 98–100°C; [h]2D5=−64.9 (c 0.9, CHCl3); IR (CHCl3):
1651, 1738, 3418 cm−1; 1H NMR (CDCl3): l 0.98 (d, 3H,
J=6.4 Hz), 1.68 (s, 3H), 3.05 (s, 3H), 3.44–3.60 (dq, 1H,
J=2.9, 6.4 Hz), 4.12 (d, 1H, J=16.6 Hz), 4.30 (d, 1H,
J=16.6 Hz), 5.46 (d, 1H, J=2.9 Hz), 7.10–7.50 (m, 5H),
8.75 (bs, 1H); 13C NMR (CDCl3): 11.7, 20.9, 33.4, 58.6,
58.8, 70.7, 98.7, 125.0, 127.2, 127.9, 136.3, 166.1, 172.1.
Anal. calcd for C15H19NO5: C, 61.42; H, 6.53; N, 4.78.
Found: C, 61.70; H, 6.72; N, 4.99%.
3. Conclusion
It must be emphasized that the acid-catalyzed hydrolysis
regenerates hemiketal as the only other product, which
was recycled. Thus, we have demonstrated an efficient use
of this (−)-ephedrine derived chiral auxiliary, which
significantly improves the practical scope of large-scale
preparations of enantiopure 3-hydroxy-cis-b-lactams,
one of which, 8a, is a key intermediate in the synthesis
of the taxol side-chain.3,8
4. Experimental
4.1. General
4.4. Typical procedure for synthesis of 6a and 7a
To a stirred solution of 4 (1.172 g, 4 mmol) in
dichloromethane (15 mL) was added triethylamine (3.34
mL, 24 mmol) and 5a (0.760 g, 3.6 mmol) at 0°C. To the
resulting solution was added triphosgene (0.831 g, 2.8
mmol) solution in dichloromethane (10 mL) dropwise
over a period of 15 min. The reaction mixture was allowed
to warm up to room temperature and stirred overnight.
The reaction mixture was then diluted with
dichloromethane (10 mL) and washed successively with
water (2×15 mL), sat. NaHCO3 (2×15 mL), brine (2×15
mL). Organic layer was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue on
purification by flash column chromatography (PE/EA,
3:2) gave more polar compound 6a (610 mg, 35%) and
less polar compound 7a (610 mg, 35%).
1H and 13C NMR spectra were recorded in a CDCl3
solution on a Bruker AC 200 or MSL 300 spectrometers
and chemical shifts are reported in ppm downfield from
1
tetramethylsilane for H NMR. Infrared spectra were
recorded on Perkin–Elmer Infrared Spectrophotometer,
Model 599-B or Shimadzu FTIR-8400 using sodium
chloride optics. Melting points were determined on a
Thermonik Campbell melting point apparatus and were
uncorrected. The microanalyses were performed on a
Carlo-Erba, CHNS-O EA 1108 Elemental analyzer.
Optical rotations were recorded on a JASCO-181 digital
Polarimeter under standard conditions.
4.2. Preparation of ethyl (2S,5S,6R)-[(2,4,6-trimethyl-3-
oxo-6-phenylmorpholin-2yl)oxy]acetate
4.4.1.
(3R,4S,2%S,5%S,6%R)-1-(4-Methoxyphenyl)-4-
To a suspension of sodium hydride (108 mg, 4.5 mmol)
in DMF (2 mL) and THF (2 mL) at 0°C was added methyl
hemiketal solution (705 mg, 3 mmol) dropwise in DMF
(2 mL) and THF (2 mL) and the resulting solution was
stirred at 0°C for 10 min. Ethyl bromoacetate (0.33 mL,
3 mmol) was then added dropwise and the resulting
solution was heated at 70°C for 16 h. Ice was added to
the reaction mixture. Ethyl acetate (15 mL) and water (15
mL) were added and organic layer was separated. Organic
layer was washed with water (3×15 mL), brine (3×15 mL),
dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue upon purification by
column chromatography PE/EA (1:1) furnished the ester
as a white solid (750 mg, 78%); mp 87–89°C; [h]2D5=−80.7
(c 1.1, CHCl3); IR 1659, 1753 cm−1; 1H NMR l 0.96 (d,
3H, J=6.3 Hz), 1.11 (t, 3H, J=7.3 Hz), 1.67 (s, 3H), 3.04
(s, 3H), 3.43–3.53 (dq, 1H, J=2.9, 6.3 Hz), 3.90–4.04 (q,
2H, J=7.3 Hz), 4.18 (s, 2H), 5.62 (d, 1H, J=2.9 Hz),
7.20–7.47 (m, 5H); 13C NMR l 12.2, 13.9, 21.4, 33.6, 59.0,
phenyl-3-[(2%,4%,5%-trimethyl-3%-oxo-6%-phenylmorpholin-2%-
yl)oxy]azetidin-2-one, 6a. Isolated as a white solid; yield
35%; mp 113–115°C; [h]2D5=−51.0 (c 0.9, CHCl3); IR
(CHCl3): 1649, 1751 cm−1; 1H NMR (CDCl3): l 0.84 (d,
3H, J=6.8 Hz), 1.70 (s, 3H), 2.89 (s, 3H), 3.15–3.30 (dq,
1H, J=2.9, 6.8 Hz), 3.71 (s, 3H), 4.63 (d, 1H, J=2.9 Hz),
5.00 (d, 1H, J=5.4 Hz), 5.36 (d, 1H, J=5.4 Hz), 6.73 (d,
2H, J=8.8 Hz), 7.10–7.50 (m, 12H); 13C NMR (CDCl3):
12.2, 23.4, 33.5, 55.4, 58.9, 62.3, 71.0, 76.0, 99.9, 114.3,
118.7, 125.6, 127.8, 128.4, 130.9, 133.8, 137.1, 156.3,
164.3, 165.2; MS: m/z 486 (M+). Anal. calcd for
C29H30N2O5: C, 71.59; H, 6.21; N, 5.76. Found: C, 71.80;
H, 6.00; N, 5.98%.
4.4.2.
(3S,4R,2%S,5%S,6%R)-1-(4-Methoxyphenyl)-4-
phenyl-3-[(2%,4%,5%-trimethyl-3%-oxo-6%-phenylmorpholin-2%-
yl)oxy]azetidin-2-one, 7a. Isolated as a white solid; yield
35%; mp 108–110°C; [h]2D5=−189.4 (c 1.4, CHCl3); IR
(CHCl3): 1649, 1751 cm−1; H NMR (CDCl3): l 0.79
1

B. A. Shinkre et al. / Tetrahedron: Asymmetry 14 (2003) 453–459
457
(d, 3H, J=6.4 Hz), 1.50 (s, 3H), 2.87 (s, 3H), 2.89–
3.05 (dq, 1H, J=2.9, 6.4 Hz), 3.71 (s, 3H), 4.57 (d,
1H, J=2.9 Hz), 5.16 (d, 1H, J=4.9 Hz), 5.57 (d, 1H,
J=4.9 Hz), 6.75 (d, 2H, J=8.3 Hz), 7.09–7.50 (m,
12H); 13C NMR (CDCl3): 12.0, 22.2, 33.1, 55.2, 58.8,
63.0, 70.6, 77.7, 98.5, 114.1, 118.6, 125.4, 127.4,
128.0, 128.6, 130.6, 134.3, 136.8, 157.0, 163.7, 165.3;
MS: m/z 486 (M+). Anal. calcd for C29H30N2O5: C,
71.59; H, 6.21; N, 5.76. Found: C, 71.83; H, 6.45; N,
5.99%.
4.4.6. (3S,4R,2%S,5%S,6%R)-1,4-Di-(4-methoxyphenyl)-3-
[(2%,4%,5%-trimethyl-3%-oxo-6%-phenylmorpholin-2%-yl)oxy]-
azetidin-2-one, 7c. Isolated as a white solid; yield
23%; mp 207–208°C; [h]2D5=−170.9 (c 2.0, CHCl3); IR
1
(CHCl3): 1649, 1747 cm−1; H NMR (CDCl3): l 0.80
(d, 3H, J=6.4 Hz), 1.49 (s, 3H), 2.90 (s, 3H), 2.96–
3.11 (dq, 1H, J=2.9, 6.4 Hz), 3.72 (s, 3H), 3.84 (s,
3H), 4.57 (d, 1H, J=2.9 Hz), 5.12 (d, 1H, J=4.9
Hz), 5.55 (d, 1H, J=4.9 Hz), 6.75 (d, 2H, J=8.8
Hz), 6.92 (d, 2H, J=8.8 Hz), 7.06–7.45 (m, 9H); 13C
NMR (CDCl3): 12.1, 22.5, 33.4, 55.2, 55.3, 59.0, 62.6,
70.7, 77.6, 98.6, 113.6, 114.2, 118.7, 125.4, 126.1,
127.5, 128.2, 129.9, 130.7, 137.0, 156.1, 159.6, 163.9,
165.5; MS: m/z 516 (M+). Anal. calcd for
C30H32N2O6: C, 69.75; H, 6.24; N, 5.42. Found: C,
69.96; H, 6.48; N, 5.70%.
Other b-lactams 6b–d and 7b–d were prepared using
the similar procedure and both the diastereomers
were separated by flash column chromatography.
4.4.3.
(3R,4S,2%S,5%S,6%R)-4-(4-Methoxyphenyl)-1-
phenyl-3-[(2%,4%,5%-trimethyl-3%-oxo-6%-phenylmorpholin-2%-
yl)oxy]azetidin-2-one, 6b. Isolated as a gum; yield
36%; [h]2D5=−64.4 (c 0.9, CHCl3); IR (CHCl3): 1649,
4.4.7.
(3R,4S,2%S,5%S,6%R)-1,4-Diphenyl-3-[(2%,4%,5%-
trimethyl-3%-oxo-6%-phenylmorpholin-2%-yl)oxy]azetidin-2-
one, 6d. Isolated as a gum; yield 36%; [h]2D5=−61.0 (c
1
1755 cm−1; H NMR (CDCl3): l 0.85 (d, 3H, J=6.4
1
1.0, CHCl3); IR (CHCl3): 1649, 1753 cm−1; H NMR
Hz), 1.73 (s, 3H), 2.91 (s, 3H), 3.16–3.33 (dq, 1H,
J=2.9, 6.4 Hz), 3.80 (s, 3H), 4.63 (d, 1H, J=2.9 Hz),
4.99 (d, 1H, J=5.4 Hz), 5.34 (d, 1H, J=5.4 Hz), 6.79
(d, 2H, J=8.8 Hz), 6.90–7.50 (m, 12H); 13C NMR
(CDCl3): 12.1, 23.4, 33.5, 55.2, 58.9, 61.9, 71.0, 75.8,
100.0, 113.9, 117.5, 124.0, 125.5, 125.6, 127.7, 128.4,
128.9, 129.7, 137.1, 137.4, 159.8, 165.1, 165.3; MS
m/z 486 (M+). Anal. calcd for C29H30N2O5: C, 71.59;
H, 6.21; N, 5.76. Found: C, 71.85; H, 6.4; N, 5.96%.
(CDCl3): l 0.84 (d, 3H, J=6.3 Hz), 1.72 (s, 3H), 2.88
(s, 3H), 3.15–3.30 (dq, 1H, J=2.4, 6.3 Hz), 4.60 (d,
1H, J=2.4 Hz), 5.03 (d, 1H, J=5.4 Hz), 5.37 (d, 1H,
J=5.4 Hz), 6.94–7.50 (m, 15H); 13C NMR (CDCl3):
12.4, 23.6, 33.7, 59.2, 62.5, 71.4, 76.2, 100.2, 117.8,
124.4, 125.9, 127.8, 128.5, 129.1, 129.3, 134.0, 136.9,
137.0, 165.1, 165.5; MS: m/z 456 (M+). Anal. calcd
for C28H28N2O4: C, 73.66; H, 6.18; N, 6.13. Found:
C, 73.88; H, 6.44; N, 6.36%.
4.4.8.
(3S,4R,2%S,5%S,6%R)-1,4-Diphenyl-3-[(2%,4%,5%-
4.4.4.
(3S,4R,2%S,5%S,6%R)-4-(4-Methoxyphenyl)-1-
trimethyl-3%-oxo-6%-phenylmorpholin-2%-yl)oxy]azetidin-2-
one, 7d. Isolated as a white solid; yield 29%; mp
99–100°C; [h]2D5=−194.6 (c 1.5, CHCl3); IR (CHCl3):
1649, 1753 cm−1; 1H NMR (CDCl3): l 0.79 (d, 3H,
J=6.8 Hz), 1.51 (s, 3H), 2.88 (s, 3H), 2.90–3.03 (dq,
1H, J=3.4, 6.8 Hz), 4.55 (d, 1H, J=3.4 Hz), 5.21 (d,
1H, J=4.9 Hz), 5.60 (d, 1H, J=4.9 Hz), 6.95–7.55
(m, 15H); 13C NMR (CDCl3): 12.2, 22.4, 33.3, 59.1,
63.1, 70.9, 77.9, 98.8, 117.5, 124.2, 125.6, 127.6,
128.2, 128.8, 129.0, 134.5, 137.1, 137.3, 164.5, 165.6;
MS: m/z 456 (M+). Anal. calcd for C28H28N2O4: C,
73.66; H, 6.18; N, 6.13. Found: C, 73.90; H, 6.42; N,
6.35%.
phenyl-3-[(2%,4%,5%-trimethyl-3%-oxo-6%-phenylmorpholin-2%-
yl)oxy]azetidin-2-one, 7b. Isolated as a white solid;
yield 24%; mp 204–205°C; [h]2D5=−181.5 (c 0.6,
CHCl3); IR (CHCl3): 1649, 1755 cm−1; 1H NMR
(CDCl3): l 0.81 (d, 3H, J=6.8 Hz), 1.50 (s, 3H), 2.91
(s, 3H), 2.96–3.09 (dq, 1H, J=2.9, 6.8 Hz), 3.84 (s,
3H), 4.57 (d, 1H, J=2.9 Hz), 5.17 (d, 1H, J=4.9
Hz), 5.57 (d, 1H, J=4.9 Hz), 6.92 (d, 2H, J=8.3
Hz), 7.00–7.47 (m, 12H); 13C NMR (CDCl3): 12.2,
22.5, 33.4, 55.2, 59.0, 62.6, 70.8, 77.6, 98.7, 113.6,
117.5, 124.1, 125.4, 126.0, 127.5, 128.2, 129.0, 129.9,
136.9, 137.1, 159.7, 164.6, 165.5; MS: m/z 486 (M+).
Anal. calcd for C29H30N2O5: C, 71.59; H, 6.21; N,
5.76. Found C, 71.80; H, 6.48; N, 5.98%.
4.5. Preparation of 3-hydroxy-cis-b-lactams 8 and 9
4.4.5. (3R,4S,2%S,5%S,6%R)-1,4-Di-(4-methoxyphenyl)-3-
[(2%,4%,5%-trimethyl-3%-oxo-6%-phenylmorpholin-2%-yl)oxy]-
azetidin-2-one, 6c. Isolated as a gum; yield 42%;
[h]2D5=−78.5 (c 1.3, CHCl3); IR (CHCl3): 1649, 1747
4.5.1. Typical procedure for hydrolysis of b-lactam, 7a to
(3S,4R)-1-(4-methoxyphenyl)-4-phenyl-3-hydroxyaze-
tidin-2-one, 9a. To a stirred solution of 7a (0.243 g, 0.5
mmol) in a mixture of THF (5 mL) and water (1 mL)
was added PTSA (0.951 g, 5 mmol) and refluxed for 10
h. THF was then removed under reduced pressure and
reaction mixture was then diluted with water (5 mL).
Solid NaHCO3 was added to the reaction mixture until
basic pH and extracted with dichloromethane (3×10
mL). Combined organic layers were washed with brine
(2×10 mL), dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure and residue on
purification by column chromatography PE/EA (1:1)
gave 9a (0.121 g, 90%) as a white solid and recovered
chiral auxiliary 3 (0.103 g, 88%).
1
cm−1; H NMR (CDCl3): l 0.84 (d, 3H, J=6.4 Hz),
1.72 (s, 3H), 2.91 (s, 3H), 3.16–3.32 (dq, 1H, J=2.9,
6.4 Hz), 3.70 (s, 3H), 3.80 (s, 3H), 4.63 (d, 1H, J=
2.9 Hz), 4.95 (d, 1H, J=5.3 Hz), 5.33 (d, 1H, J=5.3
Hz), 6.72 (d, 2H, J=8.8 Hz), 6.80 (d, 2H, J=8.8
Hz), 7.02–7.60 (m, 9H); 13C NMR (CDCl3): 12.2,
23.4, 33.5, 55.3, 55.4, 59.0, 62.0, 71.0, 75.9, 100.0,
113.9, 114.4, 118.8, 125.6, 125.8, 127.7, 128.4, 129.8,
131.0, 137.2, 156.3, 159.9, 164.5, 165.3; MS: m/z 516
(M+). Anal. calcd for C30H32N2O6: C, 69.75; H, 6.24;
N, 5.42. Found: C, 69.98; H, 6.49; N, 5.71%.

458
B. A. Shinkre et al. / Tetrahedron: Asymmetry 14 (2003) 453–459
4.5.2. (3S,4R)-1-(4-Methoxyphenyl)-4-phenyl-3-hydroxy-
azetidin-2-one, 9a. Isolated as a white solid; yield 90%;
mp 201–202°C; [h]D25=−178.0 (c 0.9, CHCl3); IR
(CHCl3): 1713, 3315 cm−1; 1H NMR (CDCl3): l 2.87 (d,
1H, J=6.9 Hz), 3.76 (s, 3H), 5.20 (dd, 1H, J=5.4, 6.9
Hz), 5.27 (d, 1H, J=5.4 Hz), 6.80 (d, 2H, J=8.8 Hz),
7.23–7.55 (m, 7H); 13C NMR (CDCl3): 55.5, 62.3,
77.26, 114.5, 118.9, 127.5, 129.0, 129.1, 130.6, 133.2,
156.5, 165.4; MS: m/z 269 (M+). Anal. calcd for
C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C,
71.60; H, 5.81; N, 5.35%.
References
1. (a) Nagahara, T.; Kametani, T. Heterocycles 1987, 25,
729; (b) Thomas, R. C. In Recent Progress in the Chemi-
cal Synthesis of Antibiotics; Lukac, G.; Ohno, M., Eds.;
Springer-Verlag: Berlin, 1990; p. 553; (c) Paloma, C. In
Recent Progress in the Chemical Synthesis of Antibiotics;
Lukac, G.; Ohno, M., Eds.; Springer-Verlag: Berlin,
1990; p. 565; (d) Van der Steen, F. H.; Van Koten, G.
Tetrahedron 1991, 47, 7503; (e) Durckheimer, W.; Blum-
bach, J.; Lattrell, R.; Scheunemann, K. H. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 180.
Specific rotation of recovered chiral auxiliary 3: [h]2D5=
−107.6 (c 1.4, CHCl3); [(lit.14 [h]D25=−107.4 (c 1.1,
CHCl3)].
2. (a) Manhas, M. S.; Amin, S. G.; Bose, A. K. Heterocycles
1976, 5, 699; (b) Ojima, I. In The Chemistry of i-Lac-
tams; Georg, G. I., Ed.; VCH: New York, 1993; p. 197;
(c) Ojima, I. Acc. Chem. Res. 1995, 28, 383.
3. Ojima, I.; Habus, I.; Zhao, M.; Georg, G. I.; Jayasinghe,
Other hydroxy b-lactams 8a and 9b–d were prepared
L. R. J. Org. Chem. 1991, 56, 1681.
from 6a and 7b–d, respectively, using
a similar
4. Georg, G. I.; Harriman, G. C. B.; Hepperle, M.; Clowers,
J. S.; Vander Velde, D. G.; Himes, R. H. J. Org. Chem.
1996, 61, 2664 and references cited therein.
procedure.
4.5.3. (3R,4S)-1-(4-Methoxyphenyl)-4-phenyl-3-hydroxy-
azetidin-2-one, 8a. Isolated as a white solid; yield 90%;
mp 196–197°C; [h]D25=+180.0 (c 0.4, CHCl3); IR
(CHCl3): 1713, 3315 cm−1; 1H NMR (CDCl3): l 2.87 (d,
1H, J=6.9 Hz), 3.76 (s, 3H), 5.20 (dd, 1H, J=5.4, 6.9
Hz), 5.27 (d, 1H, J=5.4 Hz), 6.80 (d, 2H, J=8.8 Hz),
7.23–7.55 (m, 7H); MS: m/z 269 (M+). Anal. calcd for
C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C,
71.60; H, 5.90; N, 5.45%.
5. (a) Rowinsky, E. K.; Casenave, L. A.; Donehower, R. C.
J. Natl. Cancer Inst. 1990, 82, 1247; (b) Zee-Cheng, R.
K.-Y.; Cheng, C. C. Drugs of the future 1986, 11, 45. For
recent reviews of the chemistry of Taxol, see: (c)
Kingston, D. G. I. Pharm. Ther. 1991, 52, 1; (d) Suffiness,
M.; Cordell, G. A. The Alkaloids. Chemistry and Pharma-
cology, in the Alkaloids, Brossi, A., Ed.; Academic: New
York, 1985; Vol. 25, p. 3; (e) Nicolaou, K. C.; Guy, R.
K.; Pitsinos, E. N.; Wrasildo, W. Angew. Chem., Int. Ed.
Engl. 1994, 33, 15; (f) Boa, A. N.; Jenkins, P. R.;
Lawrence, N. J. Contemporary Org. Synth. 1994, 1, 47.
6. (a) Umezawa, H.; Aoyagi, T.; Suda, H.; Hamada, M.;
Takeuchi, T. J. Antibiot. 1976, 29, 97; (b) Umezawa, H.
In Small Molecular Immunomodifiers of Microbial Origin.
Fundamental and Clinical Studies of Bestatin; Umezawa,
H., Ed.; Pergamon: Oxford, 1981; (c) Umezawa, H. Drug
Exptl. Clin. Res. 1984, 10, 519; (d) Miura, K.; Sawa, T.;
Takeuchi, T.; Umezawa, H. J. Antibiot. 1986, 39, 734.
7. Blomgren, H.; Wasserman, J. Canc. Lett. 1981, 11, 303.
8. (a) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y.
H.; Sun, C. M.; Brigaud, T. Tetrahedron 1992, 48, 6985;
(b) Georg, G. I.; Cheruvallath, Z. S.; Harriman, G. C. B.;
Hepperle, M.; Park, H. Bioorg. Med. Chem. Lett. 1993, 3,
2467; (c) Ojima, I.; Zucco, M.; Duclos, O.; Kuduk, S. D.;
Sun, C. M.; Park, Y. H. Bioorg. Med. Chem. Lett. 1993,
3, 2479.
4.5.4. (3S,4R)-4-(4-Methoxyphenyl)-1-phenyl-3-hydroxy-
azetidin-2-one, 9b. Isolated as a white solid; yield 85%;
mp 212–213°C; [h]D25=−173.7 (c 1.0, CHCl3); IR
1
(CHCl3): 1713, 3315 cm−1; H NMR (CDCl3): l 2.65
(bs, 1H), 3.82 (s, 3H), 5.18 (d, 1H, J=5.4 Hz), 5.29 (d,
1H, J=5.4 Hz), 6.95 (d, 2H, J=8.3 Hz), 7.01–7.45 (m,
7H). Anal. calcd for C16H15NO3: C, 71.36; H, 5.61; N,
5.20. Found: C, 71.63; H, 5.89; N, 5.48%.
4.5.5. (3S,4R)-1,4-Di-(4-methoxyphenyl)-3-hydroxyaze-
tidin-2-one, 9c. Isolated as a white solid; yield 88%; mp
132–133°C; [h]2D5=−179.1 (c 2.2, CHCl3); IR (CHCl3):
1
1728, 3310 cm−1; H NMR (CDCl3): l 3.04 (bs, 1H),
3.75 (s, 3H), 3.79 (s, 3H), 5.15 (d, 1H, J=5.3 Hz), 5.21
(d, 1H, J=5.3 Hz), 6.79 (d, 2H, J=8.8 Hz), 6.92 (d,
2H, J=8.7 Hz), 7.10–7.40 (m, 4H). Anal. calcd for
C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C,
68.50; H, 5.82; N, 4.87%.
9. (a) Manhas, M. S.; Amin, S. G.; Chawla, H. P. S.; Bose,
A. K. J. Heterocycl. Chem. 1978, 15, 601; (b) Nagao, Y.;
Kumagai, T.; Takao, S.; Abe, T.; Ochiai, M.; Inoue, Y.;
Taga, T.; Fujita, E. J. Org. Chem. 1986, 51, 4737; (c)
Wagle, D. R.; Garai, C.; Chiang, J.; Monteleone, M. G.;
Kurys, B. E.; Strohmeyer, T. W.; Hegde, V. R.; Manhas,
M. S.; Bose, A. K. J. Org. Chem. 1988, 53, 4227; (d)
Palomo, C.; Cossio, F. P.; Cuevas, C. Tetrahedron Lett.
1991, 32, 3109; (e) Borer, B. C.; Balogh, D. W. Tetra-
hedron Lett. 1991, 32, 1039.
4.5.6. (3S,4R)-1,4-Diphenyl-3-hydroxyazetidin-2-one, 9d.
Isolated as a white solid; yield 84%; mp 216–217°C;
[h]2D5=−188.4 (c 0.9, CHCl3); IR (CHCl3): 1713, 3325
1
cm−1; H NMR (CDCl3): l 2.65 (bs, 1H), 5.21 (d, 1H,
J=5.4 Hz), 5.33 (d, 1H, J=5.4 Hz), 6.90–7.55 (m,
10H). Anal. calcd for C15H13NO2: C, 75.30; H, 5.48; N,
5.85. Found: C, 75.50; H, 5.69; N, 5.97%.
10. (a) Holton, R. A.; Liu, J. H. Bioorg. Med. Chem. Lett.
1993, 3, 2475; (b) Palomo, C.; Arrieta, A.; Cossio, F. P.;
Aizpurua, J. M.; Mielgo, A. I.; Lopez, M. C.;
Aurrekoetxea, N. Tetrahedron Lett. 1990, 31, 6429.
11. (a) Basak, A.; Mahato, T.; Bhattaacharya, G.; Mukher-
jee, B. Tetrahedron Lett. 1997, 38, 643; (b) Brieva, R.;
Crich, J. Z.; Sih, C. J. J. Org. Chem. 1993, 58, 1068.
Acknowledgements
One of the authors (B.A.S.) thanks CSIR for the finan-
cial support.

B. A. Shinkre et al. / Tetrahedron: Asymmetry 14 (2003) 453–459
459
3
,
,
12. (a) Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B.
M. Synlett 1992, 749; (b) Jayaraman, M.; Nandi, M.;
Sathe, K. M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron: Asymmetry 1993, 4, 609; (c) Jayaraman, M.;
Deshmukh, A. R. A. S.; Bhawal, B. M. J. Org. Chem.
1994, 59, 932; (d) Jayaraman, M.; Srirajan, V.; Desh-
mukh, A. R. A. S.; Bhawal, B. M. Tetrahedron 1996, 52,
3741; (e) Srirajan, V.; Puranik, V. G.; Deshmukh, A. R.
A. S.; Bhawal, B. M. Tetrahedron 1996, 52, 5579; (f)
Srirajan, V.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron 1996, 52, 5585; (g) Jayaraman, M.; Puranik,
V. G.; Bhawal, B. M. Tetrahedron 1996, 52, 9005; (h)
Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron 1996, 52, 8989; (i) Srirajan, V.; Deshmukh,
A. R. A. S.; Puranik, V. G.; Bhawal, B. M. Tetrahedron:
Asymmetry 1996, 7, 2733; (j) Joshi, S. N.; Deshmukh, A.
R. A. S.; Bhawal, B. M. Tetrahedron: Asymmetry 2000,
11, 1477.
15.103(5), c=29.301(9) A, V=2551.2(14) A , Z=4,
D
calcd=1.267 mg m−3, v=0.087 mm−1, F(000)=1032,
T=293 K. Data were collected on SMART APEX CCD
Single Crystal X-ray diffractometer using Mo-Ka radia-
tion (u=0.7107 A) to a maximum q range of 23.27°. The
,
structure was solved by direct methods using SHELXTL.
Least squares refinement of scale, positional and
anisotropic thermal parameters for non hydrogen atom
converged to R=0.0373. Rw=0.0748 for [I>2|(I)], 3673
unique observed reflections out of 18110 measured. All
the data were corrected for Lorentzian, polarisation and
absorption effects. SHELX-9716 was used for structure
solution and full-matrix least-squares refinement on F2.
Hydrogen atoms were included in the refinement as per
the riding model. Largest diff. peak and hole 0.115 and
−0.110 e A−3. ORTEP diagram of the molecule along
,
with the crystallographic numbering of atoms. Ellipsoids
are drawn with 50% probability. Crystallographic data
(excluding structure factors) for the structure 7b in this
paper has been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication num-
ber CCDC 200549.
13. Pansare, S. V.; Ravi, R. G.; Jain, R. P. J. Org. Chem.
1998, 63, 4120.
14. Pansare, S. V.; Shinkre, B. A.; Bhattacharyya, A. Tetra-
hedron 2002, 58, 8985.
16. Sheldrick, G. M. SHELX-97 program for crystal struc-
ture solution and refinement, University of Gottingen,
Germany, 1997.
15. X-Ray crystal data for 7b: C29H30N2O5: colorless needles
(0.57×0.11×0.03 mm grown from methanol). M=486.55,
orthorhombic, space group P212121, a=5.765(2), b=