An efficient synthesis of enantiomerically pure 3-hydroxy-β-lactams via zinc induced removal of a chiral auxiliary

Article abstract of DOI:10.1016/S0957-4166(00)00098-7

The diastereoselective synthesis of various β-lactams 6a-d and 7a-d has been achieved using a chiral acid derived from (+)-3-carene. An efficient zinc induced cleavage of the o-halo ether linkage of these β-lactams to give enantiomerically pure 3-hydroxy-

Full text of DOI:10.1016/S0957-4166(00)00098-7

Tetrahedron: Asymmetry 11 (2000) 1477±1485
An ecient synthesis of enantiomerically pure
3-hydroxy-b-lactams via zinc induced removal
of a chiral auxiliary
Sudhir N. Joshi, A. R. A. S. Deshmukh and B. M. Bhawal*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received 31 May 1999; revised 2 March 2000; accepted 3 March 2000
Abstract
The diastereoselective synthesis of various b-lactams 6a±d and 7a±d has been achieved using a chiral acid
derived from (+)-3-carene. An ecient zinc induced cleavage of the o-halo ether linkage of these b-lactams
to give enantiomerically pure 3-hydroxy-cis-b-lactams 8a,b and 9a±d is described. # 2000 Elsevier Science
Ltd. All rights reserved.
1. Introduction
Besides being used for the synthesis of a variety of b-lactam antibiotics,1 the b-lactam skeleton
has been recognized as a useful precursor for various non-b-lactam derivatives (ꢀ-lactam synthon
approach).2 It has been shown that suitably substituted 3-hydroxy-b-lactams can serve as a synthetic
equivalent for the phenylisoserine3 side chain of taxol or can be directly coupled with baccatin
III4 to give taxol. The syntheses of suitably substituted (3R,4S) 3-hydroxy-b-lactams by dia-
stereoselective cycloaddition reactions,3 6 borohydride reductions7 of 3-ketoazetidinones and
resolutions8 of (þ)-3-hydroxy-b-lactams have been reported.
In our continued e€orts towards the asymmetric synthesis of b-lactams and their use as
synthons,9 we have recently reported the use of a chiral auxiliary derived from readily available
and naturally abundant (+)-3-carene9f for the taxol side chain. However, oxidative cleavage of the
chiral auxiliary using MCPBA limited the use of this methodology in large-scale preparations.
We herein report a solution to this problem by structural modi®cation of the chiral auxiliary,
which permits its removal under mild conditions.
* Corresponding author: Fax: +91-20-5893153; e-mail: bhawal@dalton.ncl.res.in
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00098-7

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2. Results and discussion
The acid 3 was obtained from (+)-3-carene 1 by NBS reaction10 in the presence of ethylene
glycol followed by Jones oxidation of bromo alcohol 2. The acid 3 was converted to acid chloride
4 in almost quantitative yield by using thionyl chloride (Scheme 1). The acid chloride 4, on
cycloaddition reaction with various imines 5 in the presence of triethylamine, furnished a dia-
stereomeric mixture of cis-b-lactams 6a±d and 7a±d in good yields (Scheme 2, Table 1). In most of
the cases the diastereomers were separated either by crystallization or column chromatography.
Scheme 1. (i) NBS/ethylene glycol, 0ꢀC, 4 h; (ii) Jones oxidation; (iii) SOCl2/benzene, re¯ux, 3 h
Scheme 2.
Table 1
Synthesis of cis-b-lactams 6a±d and 7a±d from acid chloride 4 and imines 5a±d
The cleavage of the chiral auxiliary was e€ected by reacting pure diastereomers 6a,b and 7a±d
with zinc/acetic acid (Boord reaction11) under re¯ux for 30 min to give corresponding enantio-
merically pure 3-hydroxy-cis-b-lactams 8a,b and 9a±d in nearly quantitative yields (Scheme 3,
Table 2). The (+)-3-carene formed in the reaction by cleavage of the chiral auxiliary was also
isolated and characterized. The formation of 3-hydroxy-b-lactams 8a,b and 9a±d was con®rmed
from their spectral data (IR, 1H NMR). The absolute con®guration of the b-lactams 8 and 9 was

S. N. Joshi et al. / Tetrahedron: Asymmetry 11 (2000) 1477±1485
1479
Scheme 3.
Table 2
Synthesis of 3-hydroxy-b-lactams 8a,b and 9a±d from optically pure diastereomers 6a,b and 7a±d
assigned as (3R,4S) and (3S,4R), respectively, by comparing their physical data as well as speci®c
rotations with some of the compounds 8b and 9b,d reported in the literature.6e,8b,9f
3. Conclusion
It must be emphasized that the zinc-mediated cleavage of the chiral auxiliary regenerates (+)-
3-carene as the only other product, which, in principle, should permit recycling of the chiral
auxiliary. Thus, we have demonstrated that a small change in the design of a chiral pool-derived

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S. N. Joshi et al. / Tetrahedron: Asymmetry 11 (2000) 1477±1485
auxiliary signi®cantly improves the practical scope of the large-scale preparation of enantiopure
3-hydroxy-cis-b-lactams, one of which, 9a, is a key intermediate for the taxol side-chain.3,5
4. Experimental
4.1. General
1H NMR spectra were recorded in CDCl3 solution on a Bruker AC 200 and MSL-300 spec-
trometer and chemical shifts are reported in ppm down®eld from tetramethylsilane. 13C NMR
spectra were recorded in CDCl3 solution on Bruker AC 200 instruments and chemical shifts are
reported in ppm, relative to the centerline of CDCl3 (77.0 ppm). Infrared spectra were recorded
on a Perkin±Elmer Infracord Specrophotometer Model 599-B using sodium chloride optics.
Melting points were determined on a Thermonik Campbell point apparatus and are uncorrected.
The microanalysis was 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 (10S,30R,40R,60R)-2-[40-bromo-30,70,70-trimethylbicyclo(4.1.0)hept-30-yloxy]ethan-
1-ol 2
To a stirred solution of (+)-3-carene (1.36 g, 10 mmol) and ethylene glycol (31 mL, 50 mmol) in
dichloromethane (30 mL), powdered NBS (2.23 g, 12.5 mmol) was added in small portions over a
period of 30 min at 0ꢀC. The reaction mixture was allowed to warm-up to room temperature and
stirred for a further 4 h. After the completion of the reaction (TLC), cold water (50 mL) was
added to the reaction mixture and extracted with dichloromethane (3Â30 mL). The combined
extracts were washed with sat. NaHSO3 (15 mL), water (20 mL), brine (15 mL) and dried over
anhydrous Na2SO4 and ®ltered. The ®ltrate was concentrated under reduced pressure and the
residue was puri®ed by column chromatography (silica gel, 60±120, pet. ether/ethyl acetate) to
give 1.24 g (45%) of pure bromo alcohol 2 as a pale yellow liquid. ‰ꢁŠ2D5=^33.45 (c 1.65, CHCl3);
IR 3400 cm^1; 1H NMR (CDCl3) ꢂ 0.65±0.90 (m, 2H), 0.97 (s, 3H), 1.0 (s, 3H), 1.30±1.50 (m, 1H),
1.35 (s, 3H), 2.05±2.25 (m, 1H), 2.40±2.50 (m, 2H), 3.40±3.60 (m, 2H), 3.65±3.75 (m, 2H), 4.07 (t,
J=8 Hz, 1H); 13C NMR (CDCl3) ꢂ 15.48, 17.70, 18.32, 19.50, 21.63, 28.39, 29.97, 31.80, 59.92,
61.83, 62.04, 75.25; MS: m/z (%) 276 (M+, 3.5), 92 (100).
4.3. Preparation of (10S,30R,40R,60R)-2-[40-bromo-30,70,70-trimethylbicyclo(4.1.0)hept-30-yloxy]-
acetic acid 3
To a stirred solution of bromo alcohol 2 (276 mg, 1 mmol) in acetone (10 mL), Jones reagent
was added drop by drop at 0ꢀC until decolorization of the reagent was stopped. The reaction
mixture was further stirred for 3 h at room temperature, the green precipitate of the chromium
salt was ®ltered o€ and the excess reagent destroyed by adding isopropyl alcohol at 0ꢀC. The
solution was concentrated under vacuum and residue was extracted with ether (3Â20 mL). The
ether extract was washed with brine and dried over Na2SO4. It was then ®ltered and ®ltrate on
concentration under reduced pressure a€orded bromo acid 3 (232 mg, 80%). The pure bromo
acid was obtained by crystallization from pet. ether/ethyl acetate to give 3 as white crystals, mp 85ꢀC;
25
1
‰ꢁŠD =^72 (c 0.45, CHCl3); IR 1760, 2600, 3700 cm^1; H NMR (CDCl3) ꢂ 0.65±0.90 (m, 2H),

S. N. Joshi et al. / Tetrahedron: Asymmetry 11 (2000) 1477±1485
1481
0.98 and 1.00 (2s, 6H), 1.4 (s, 3H), 1.3±1.4 (m, 1H), 2.20 (dd, J=5.5, 10 Hz, 1H), 2.35±2.55 (m,
2H), 4.00 (m, 1H), 4.05 (d, J=18 Hz, 1H), 4.10 (d, J=18 Hz, 1H), 7.30±9.0 (bs, 1H); 13C NMR
(CDCl3) ꢂ 15.71, 17.34, 18.18, 19.55, 21.85, 28.57, 30.88, 31.99, 59.74, 59.89, 78.12; MS: m/z (%)
210 (M+^HBr, 2), 135 (82), 107 (37), 93 (100), 77 (40), 71 (52), 67 (38).
4.4. Preparation of (10S,30R,40R,60R)-2-[40-bromo-30,70,70-trimethylbicyclo(4.1.0)hept-30-yloxy]acetyl
chloride 4
A mixture of acid 3 (5.8 g, 20 mmol) and SOCl2 (2.18 mL, 30 mmol) in dry benzene (40 mL)
was re¯uxed for 3 h. The benzene was removed by distillation to give 5.240 g (85%) of acid
chloride 4, which was used as such in the next step.
4.5. Preparation of b-lactams 6a and 7a
To a stirred solution of imine 5a (2.10 g, 10 mmol) and Et3N (7.50 mL, 75 mmol) in dry
dichloromethane (50 mL), a solution of acid chloride 4 (7.70 g, 25 mmol) in dry dichloromethane
(20 mL) was added drop-wise at 0ꢀC over a period of 1 h. The reaction mixture was allowed to
warm-up to room temperature and stirred overnight. The reaction mixture was then diluted with
dichloromethane (20 mL) and washed successively with water (30 mL), sat. NaHCO3 (30 mL),
brine (25 mL) and dried over anhydrous Na2SO4. The solvent was removed by distillation under
reduced pressure and residue on column chromatography (silica gel, 60±120, pet. ether/ethyl
acetate) gave 3.38 g (70%) diastereomeric mixture of b-lactams (6a and 7a) in a ratio of 60:40
1
(HPLC and H NMR analysis). The ¯ash column chromatography (silica gel, 230±400) of the
diastereomeric mixture gave less polar compound 7a (675 mg, 20%) and more polar compound
6a (1.35 g, 40%), along with a diastereomeric mixture of 6a and 7a (1.10 g).
4.5.1. (3S,4R,10S,30R,40R,60R)-1-(4-Methoxyphenyl)-3-[40-bromo-30,70,70-trimethylbicyclo(4.1.0)-
hept-30-yloxy]-4-phenylazetidin-2-one 6a
25
ꢀ
1
Isolated as a white solid; mp 176 C; ‰ꢁŠD =^114.2 (c 0.48, CH2Cl2); IR 1752 cm^1; H NMR
(CDCl3) ꢂ 0.50±0.70 (m, 2H), 0.74 (s, 3H), 0.87 (s, 3H), 0.94 (dd, J=4.5, 14.5 Hz, 1H), 1.24 (s,
3H), 1.57 (9.5, 14.5 Hz, 1H), 2.25 (dd, J=4.5, 8.7 Hz, 2H), 3.70 (s, 3H), 3.73 (t, J=8.5 Hz, 1H),
5.05 (d, J=4.8 Hz, 1H), 5.27 (d, J=4.8 Hz, 1H), 6.73 (d, J=9 Hz, 2H), 7.24 (d, J=9 Hz), 7.29±
7.39 (m, 3H).
4.5.2. (3R,4S,10S,30R,40R,60R)-1-(4-Methoxyphenyl)-3-[40-bromo-30,70,70-trimethylbicyclo(4.1.0)-
hept-30-yloxy]-4-phenylazetidin-2-one 7a
25
ꢀ
1
Isolated as a white solid; mp 148 C; ‰ꢁŠD =+18.7 (c 0.31, CH2Cl2); IR 1755 cm^1; H NMR
(CDCl3) ꢂ 0.5±0.6 (m, 1H), 0.65±0.80 (m, 1H), 0.87 (s, 3H), 0.91 (s, 3H), 1.19 (s, 3H), 1.32
(dd, J=5, 15 Hz, 1H), 2.18 (dd, J=10, 15 Hz, 1H), 2.20±2.30 (m, 2H), 3.70 (t, J=7.5 Hz, 1H),
3.75 (s, 3H), 5.12 (d, J=5 Hz, 1H), 5.19 (d, J=5 Hz, 1H), 6.74 (d, J=9 Hz, 2H), 7.20±7.40 (m,
7H).
4.5.2.1. Data for mixture of 6a and 7a. 13C NMR (CDCl3) ꢂ 15.27, 15.40, 17.81, 18.20, 18.86,
19.36, 19.49, 21.24, 21.50, 28.42, 31.42, 31.87, 31.96, 32.08, 35.39, 59.44, 59.60, 63.07, 63.18,
77.48, 77.68, 114.31, 118.73, 128.18, 128.40, 128.48, 128.66, 130.93, 134.04, 134.31, 156.19,
164.91, 165.31. MS: m/z (%) 485 (M++2, 5), 483 (M+, 4), 268 (49), 211 (62), 135 (58), 134 (51), 120

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S. N. Joshi et al. / Tetrahedron: Asymmetry 11 (2000) 1477±1485
(80), 93 (100), 91 (89), 77 (52). Anal calcd for C26H30BrNO3: C, 64.46; H, 6.24; N, 2.89. Found:
C, 64.91; H, 6.48; N, 3.02.
Other b-lactams 6b±d and 7b±d were prepared using the same procedure except for their
method of puri®cation.
The diastereomeric mixture of b-lactams 6b and 7b (2.94 g, 65%) was separated by ¯ash
column chromatography (silica gel, 230±400), which gave polar 6b (1.32 g, 45%) and less polar 7b
(529 mg, 18%), along with a mixture of 6b and 7b (910 mg).
4.5.2.2. (3S,4R,10S,30R,40R,60R)-3-[40-Bromo-30,70,70-trimethylbicyclo(4.1.0)hept-30-yloxy]-1,4-
diphenylazetidin-2-one 6b. Isolated as a white solid; mp 159ꢀC; ‰ꢁŠD25=^100.9 (c 0.22, CH2Cl2); IR
1
1755 cm^1; H NMR (CDCl3) ꢂ 0.45±0.70 (m, 2H), 0.74 (s, 3H), 0.89 (s, 3H), 0.90±1.10 (m, 1H),
1.27 (s, 3H), 1.55±1.75 (m, 1H), 2.25 (dd, J=4.4, 8 Hz, 2H), 3.75 ( t, J=8 Hz, 1H), 5.12 (d, J=5
Hz, 1H), 5.31 (d, J=5 Hz, 1H), 7.15±7.50 (m, 10H).
4.5.2.3. (3R,4S,10S,30R,40R,60R)-3-[40-Bromo-30,70,70-trimethylbicyclo(4.1.0)hept-30-yl-oxy]-1,4-
diphenylazetidin-2-one 7b. Isolated as a white solid; mp 181ꢀC; ‰ꢁŠD25=+21 (c 0.2, CH2Cl2); IR
1
1753 cm^1; H NMR (CDCl3) ꢂ 0.50±0.65 (m, 1H), 0.65±0.80 (m, 1H), 0.90 (s, 3H), 0.95 (s, 3H),
1.20 (s, 3H), 1.20±1.40 (m, 1H), 2.00±2.40 (m, 3H), 3.70 (t, J=9 Hz, 1H), 5.18 (d, J=5 Hz, 1H),
5.25 (d, J=5 Hz, 1H), 6.95±7.50 (m, 10H).
4.5.2.4. Data for mixture of 6b and 7b. MS: m/z (%) 455 (M+2, 3), 453 (M+, 3), 238 (68), 182 (90),
135 (66), 120 (79), 93 (100), 91 (99), 77 (72), 55 (45); 13C NMR (CDCl3) ꢂ 15.25, 15.39, 17.77,
18.21, 18.83, 19.33, 19.46, 21.21, 21.47, 28.41, 31.40, 31.84, 31.93, 32.05, 59.16, 59.37, 62.91,
63.01, 76, 77.61, 117.42, 124.07, 128.18, 128.42, 128.61, 128.97, 133.87, 134.13, 137.34, 165.54,
166. Anal. calcd for C27H32BrNO4: C, 66.08; H, 6.21; N, 3.08. Found: C, 66.32; H, 6.49; N, 3.17.
The diastereomeric mixture of b-lactams 6c and 7c (3.59 g, 70%) was separated by ¯ash
column chromatography to give polar 6c (1.540 g, 43%) and less polar 7c (789 mg, 22%), along
with a mixture of 6b and 7b (1.1 g).
4.5.2.5. (3S,4R,10S,30R,40R,60R)-3-[40-Bromo-30,70,70-trimethylbicyclo(4.1.0)hept-30-yloxy]-1,4-
di-(4-methoxyphenyl)azetidin-2-one 6c. Isolated as a white solid; mp 167ꢀC; ‰ꢁŠD25=^123.6 (c 0.23,
1
CH2Cl2); IR 1751 cm^1; H NMR (CDCl3) ꢂ 0.50±0.70 (m, 2H), 0.75 (s, 3H), 0.90 (s, 3H), 0.95
(dd, J=6, 15 Hz, 1H), 1.25 (s, 3H), 1.50±1.70 (m, 1H), 2.30 (dd, J=3, 12 Hz, 2H), 3.70 (s, 3H),
3.70±3.75 (m, 1H), 3.80 (s, 3H), 5.0 (d, J=6 Hz, 1H), 5.25 (d, J=6 Hz, 1H), 6.72 (d, J=9 Hz,
2H), 6.85 (d, J=9 Hz, 2H), 7.22 (d, J=9 Hz, 2H), 7.25 (d, J=9 Hz, 2H).
4.5.2.6. (3R,4S,10S,30R,40R,60R)-3-[40-Bromo-30,70,70-trimethylbicyclo(4.1.0)hept-30-yloxy]-1,4-
di-(4-methoxyphenyl)azetidin-2-one 7c. Isolated as a white solid; mp 157ꢀC; ‰ꢁŠD25=+20 (c 0.23,
1
CH2Cl2); IR 1750 cm^1; H NMR (CDCl3) ꢂ 0.50±0.60 (m, 1H), 0.65±0.80 (m, 1H), 0.90 (s, 3H),
0.92 (s, 3H), 1.18 (s, 3H), 1.30 (dd, J=6, 12 Hz, 1H), 2.15 (dd, J=12, 15 Hz, 1H), 2.20±2.35 (m,
2H), 3.70 (s, 3H), 3.60±3.75 (m, 1H), 3.78 (s, 3H), 5.05 (d, J=4.9 Hz, 1H), 5.15 (d, J=4.9 Hz,
1H), 6.75 (d, J=9 Hz, 2H), 6.85 (d, J=9 Hz, 2H), 7.25 (d, J=8 Hz, 4H).
4.5.2.7. Data for mixture of 6c and 7c. 13C NMR (CDCl3) ꢂ 15.51, 15.69, 18.01, 18.63, 18.98,
19.60, 21.46, 21.71, 28.65, 31.64, 32.06, 55.46, 59.65, 62.98, 76, 77.70, 113.19, 114.48, 118.97,
126.19, 126.41, 130.07, 130.22, 131.19, 156.34, 159.96, 165.23, 165.58; MS: m/z (%) 515 (M++2,

S. N. Joshi et al. / Tetrahedron: Asymmetry 11 (2000) 1477±1485
1483
0.18), 513 (M+, 0.2), 241 (39), 134 (60), 121 (57), 93 (57), 77 (38). Anal. calcd for C27H32BrNO4:
C, 63.04; H, 6.27; N, 2.72. Found: C, 62.79; H, 6.31; N, 3.01.
The diastereomeric mixture of b-lactams 6d and 7d (3.05 g, 60%) was separated by ¯ash
column chromatography to o€er polar 6d (915 mg, 30%) and less polar 7d (450 mg, 15%),
along with a mixture of 6b and 7b (1.5 g).
4.5.2.8. (3S,4R,10S,30R,40R,60R)-1-(4-Methoxyphenyl)-3-[40-bromo-30,70,70-trimethylbicyclo(4.1.0)-
hept-30-yloxy]-4-(200-phenylethynyl)azetidin-2-one 6d. Isolated as a white solid; mp 158±160ꢀC;
25
1
‰ꢁŠD =^122.9 (c 1.85, CH2Cl2); IR 1750 cm^1; H NMR (CDCl3) ꢂ 0.55±0.85 (m, 2H), 0.93 (s,
3H), 0.95 (s, 3H), 1.45 (s, 3H), 1.45±1.60 (m, 1H), 2.20 (dd, J=12.5, 15 Hz, 1 H), 2.40 (dd, J=6,
10 Hz, 1H), 3.75 (s, 3H), 4.05 (t, J=10 Hz, 1H), 4.75 (dd, J=5, 10 Hz, 1H), 5.20 (d, J=5 Hz,
1H), 6.35 (dd, J=10, 15 Hz, 1H), 6.70±6.90 (m, 3H), 7.20±7.55 (m, 7H).
4.5.2.9. (3R,4S,10S,30R,40R,60R)-1-(4-Methoxyphenyl)-3-[40-bromo-30,70,70-trimethylbicyclo(4.1.0)-
hept-30-yloxy]-4-(200-phenylethenyl)azetidin-2-one 7d. Isolated as a white solid; mp 166ꢀC;
25
1
‰ꢁŠD =+33 (c 1.85, CH2Cl2); IR 1520, 1750 cm^1; H NMR (CDCl3) ꢂ 0.55±0.75 (m, 1H), 0.75±
0.95 (m, 1H), 1.00 (s, 3H), 1.05 (s, 3H), 1.35 (s, 3H), 1.50 (dd, J=5, 15 Hz, 1H), 2.20±2.50 (m,
3H), 3.75 (s, 3H), 4.05 (dd, J=8, 10 Hz, 1H), 4.75 (dd, J=5, 10 Hz, 1H), 5.15 (d, J=5 Hz, 1H),
6.45 (dd, J=10, 15 Hz, 1H), 6.70±6.95 (m, 3H), 7.20±7.60 (m, 7H).
4.5.2.10. Data for mixture of 6d and 7d. MS: m/z (%) 511 (M++2, 1.8), 509 (M+, 2), 294 (28), 236
(35), 146 (69), 115 (100), 93 (83), 91 (69), 77 (38); 13C NMR (CDCl3) ꢂ 15.36, 15.52, 17.82, 17.88,
19.35, 19.44, 19.60, 21.36, 21.70, 28.39, 31.62, 31.87, 32.01, 55.37, 58.85, 60.14, 61.71, 62.33,
77.43, 77.70, 77.87, 114.26, 118.56, 118.63, 125.11, 126.62, 126.78, 128.03, 128.14, 128.48, 128.60,
131.41, 135.76, 135.89, 136.73, 156.20, 164.70, 164.79. Anal. calcd for C28H32BrNO3: C, 65.99; H,
6.33; N, 2.75. Found: C, 65.85; H, 6.52; N, 2.70.
4.6. Preparation of 3-hydroxy-cis-b-lactams 8 and 9
4.6.1. Preparation of (3S,4R)-3-hydroxy-1-(40-methoxyphenyl)-4-phenyl-cis-b-lactam 9a
To a solution of b-lactam 7a (5 g, 10.35 mmol) in methanol (150 mL), activated Zn (6.35 g, 100
mmol) and glacial acetic acid (2.5 mL) were added with stirring. The reaction mixture was then
heated at 80ꢀC with continuous removal of methanol over a period of 3 h.
4.6.1.1. Isolation of (+)-3-carene. The distilled methanol from reaction mixture was diluted with
ice-cold water (500 mL) and extracted with pet. ether (4Â100 mL). The combined pet. ether
extract was washed with sat. NaHCO3 (50 mL), water (50 mL) and ®nally with brine (50 mL) and
dried over sodium sulphate. The solvent was removed by distillation and residue was puri®ed by
Kugelrohr distillation to give 1.26 g (90%) of pure (+)-3-carene. The IR, NMR and optical
rotation were identical with the authentic (+)-3-carene sample.
4.6.1.2. Isolation of b-lactam 9a. The residue from the reaction mixture was treated with di-
chloromethane (100 mL) and ®ltered; the solid was washed with dichloromethane (3Â50 mL).
The combined ®ltrate was successively washed with dilute HCl (5%, 50 mL), satd NaHCO3
(2Â30 mL), water (2Â40 mL), brine (20 mL)) and dried over anhydrous Na2SO4. The removal of
solvent gave 2.50 g (90%) of 9a as a white crystalline solid, mp 200±201ꢀC; ‰ꢁŠD25=^177.4 (c 1,

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S. N. Joshi et al. / Tetrahedron: Asymmetry 11 (2000) 1477±1485
CHCl3); IR 1716, 3328 cm^1; 1H NMR (CDCl3) ꢂ 2.45 (d, J=8.5 Hz, 1H), 3.75 (s, 3H), 5.20 (dd,
J=5.4, 8.8 Hz, 1H), 5.30 (d, J=5.4 Hz, 1H), 6.80 (d, J=9 Hz, 2H), 7.15±7.60 (m, 7H). Anal.
calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C, 70.84; H, 5.86; N, 5.02.
Using a similar procedure as described for 9a, the following 3-hydroxyazetidin-2-ones were
prepared.
4.6.2. (3R,4S)-1-(4-Methoxyphenyl)-4-phenyl-3-hydroxyazetidin-2-one 8a
Isolated as a white solid; mp 197±199ꢀC; ‰ꢁŠD25=+178.2 (c 0.33, CHCl3); IR 1716, 3328 cm^1;
1H NMR (CDCl3) ꢂ 3.75 (s, 3H), 5.15 (d, J=5.2 Hz, 1H), 5.25 (d, J=5.2 Hz, 1H), 6.80 (d, J=9
Hz, 2H), 7.15±7.50 (m, 7H). Anal. calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C,
71.65; H, 5.80; N, 5.49.
4.6.3. (3R,4S)-1,4-Diphenyl-3-hydroxyazetidin-2-one 8b
Isolated as a white solid; mp 217±218ꢀC; ‰ꢁŠD25=+190.9 (c 0.7, CHCl3); IR 1740, 2852, 3350
1
cm^1; H NMR (CDCl3) ꢂ 5.15 (d, J=5.4 Hz, 1H), 5.18 (d, J=5.4 Hz, 1H), 6.90±7.50 (m, 10H).
Anal. calcd for C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C, 75.14; H, 5.43; N, 5.89.
4.6.4. (3S,4R)-1,4-Diphenyl-3-hydroxyazetin-2-one 9b
Isolated as a white solid; mp 216±217ꢀC; ‰ꢁŠD25=^188.7 (c 0.39, CHCl3); IR 1716, 2852, 3328
1
cm^1; H NMR (CDCl3) ꢂ 5.15 (d, J=5.4 Hz, 1H), 5.20 (d, J=5.4 Hz, 1H), 6.80±7.55 (m, 10H).
Anal. calcd for C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C, 75.68; H, 5.65; N, 6.10.
4.6.5. (3S,4R)-1,4-Di-(4-methoxyphenyl)-3-hydroxyazetidin-2-one 9c
Isolated as a white crystalline solid; mp 132ꢀC; ‰ꢁŠD25=^181.9 (c 0.93, CHCl3); IR 1726, 2852,
1
3301 cm^1; H NMR (CDCl3) ꢂ 3.75 (s, 3H), 3.80 (s, 3H), 5.15 (dd, J=5.4, 8 Hz, 1H), 5.25 (d,
J=5.4 Hz, 1H), 6.80 (d, J=8 Hz, 2H), 6.95 (d, J=8 Hz, 2H), 7.20±7.40 (m, 4H). Anal. calcd for
C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C, 68.06; H, 5.98; N, 4.55.
4.6.6. (3S,4R)-3-Hydroxy-1-(4-methoxyphenyl)-4-(2-phenylethenyl)azetidin-2-one 9d
Isolated as a white solid; mp 156±157ꢀC; ‰ꢁŠD25=^236 (c 0.01, CH3OH); IR 1737, 3340 cm^1;
1H NMR ꢂ 3.75 (s, 3H), 4.85 (dd, J=5.2, 7.4 Hz, 1H), 5.15 (bd, J=5.2 Hz, 1H), 6.40 (dd, J=8.1,
16.1 Hz, 1H), 6.65±7.00 (m, 3H), 7.20±7.65 (m, 7H). Anal. calcd for C18H17NO3: C, 73.20; H,
5.80; N, 4.74. Found: C, 73.59; H, 6.02; N, 5.00.
Acknowledgements
We thank Dr. A. Sarkar for valuable suggestions and one of the authors (S.N.J.) thanks the
CSIR for ®nancial support.
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