Stereoselective synthesis of a new enantiopure tricyclic β-lactam derivative via a tricarbonyl(η6-arene)chromium(0) complex

Article abstract of DOI:10.1016/S0957-4166(00)00137-3

The tricyclic β-lactam 5 has been synthesized both in racemic and enantiopure form starting from the enantiomerically pure tricarbonylchromium(0) complex 1. The synthetic sequence involves the stereoselective [2+2] cycloaddition of 1 with acetoxyacetylket

Full text of DOI:10.1016/S0957-4166(00)00137-3

Tetrahedron: Asymmetry 11 (2000) 1927±1941
Stereoselective synthesis of a new enantiopure tricyclic
b-lactam derivative via a tricarbonyl(Z6-arene)chromium(0)
complex
Paola Del Buttero,a,* Clara Baldoli,a Giorgio Moltenia and Tullio Pilatib
a
Á
Dipartimento di Chimica Organica e Industriale dell' Universita e Centro CNR, Via Venezian 21, 20133 Milano, Italy
CNR-Centro per lo Studio delle Relazioni fra Struttura e Reattivita Chimica, Via C. Golgi 19, 20133 Milano, Italy
b
Á
Received 2 March 2000; accepted 5 April 2000
Abstract
The tricyclic b-lactam 5 has been synthesized both in racemic and enantiopure form starting from the
enantiomerically pure tricarbonylchromium(0) complex 1. The synthetic sequence involves the stereo-
selective [2+2] cycloaddition of 1 with acetoxyacetylketene, followed by intramolecular aromatic nucleo-
philic substitution of the ¯uorine atom. Mechanistic pathways leading to 5 are discussed. # 2000 Elsevier
Science Ltd. All rights reserved.
1. Introduction
The resistance of pathogenic bacteria to b-lactam antibiotics has an important incidence in
human infections. As a consequence, in the last few years many research groups have been
actively involved in improving the microbiological activity of antibacterial agents, as well as
®nding b-lactamase inhibitors,1 and exploring new b-lactam containing ring systems.
As part of our research aimed at the use of chiral arenechromium tricarbonyl derivatives for
the stereoselective synthesis of heterocyclic systems with potential biological activity, we have
recently reported the synthesis of enantiomerically pure azetidinones.2 5 We therefore envisaged
the opportunity of obtaining new chiral tricyclic b-lactams by exploiting the asymmetric induc-
tion, which could arise from ortho-substituted complexed arenes,6 and the nucleophilic aromatic
substitution7 activated by the Cr(CO)3 unit.
We report here our results on the synthesis of a new chiral tricyclic b-lactam 5, 3,4-benzo-6-
(4-methoxyphenyl)-2,6-oxazabicyclo[3.2.0]hept-3-en-7-one, both in racemic and enantiomerically
pure form.
* Corresponding author. E-mail: delbuttero@icil64.cilea.it
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00137-3

1928
P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
2. Results and discussion
The reaction sequence was ®rst set up on racemic substrates and then repeated on enantio-
merically pure complexes. In Scheme 1 the sequence for optically pure substrates starting from
(^)-(1R) tricarbonyl[N-(2-¯uorobenzylidene)-4-methoxyaniline]chromium 1 are reported. Imine 1
was obtained, in nearly quantitative yield, from the corresponding (^)-(1R) benzaldehyde
complex.8
Scheme 1.
The [2+2] cycloaddition of imine (þ)-1 and acetoxyacetyl chloride at 0ꢀC with Et3N in CH2Cl2
a€orded the cis b-lactam 2 as a single diastereoisomer in 94% yield (d.e.>98%). Subsequent
treatment of 2 with hydrazine in a methanolic solution gave, in 85% yield, the corresponding cis
3-hydroxy b-lactam 3, the key intermediate for the tricyclic structure. The intramolecular dis-
placement of the ¯uorine atom of 3 was carried out by treating the latter with an equimolar
amount of NaH at room temperature.
Usual work-up of the reaction mixture, followed by chromatography and crystallization, gave
rise to product 4 as a single diastereoisomer in 50% yield, whose spectroscopic and analytical
data are consistent with the proposed tricyclic structure. Finally, uncomplexed 5 was obtained
quantitatively by exposure of 4 to air and sunlight in CH2Cl2 solution.
A single crystal of racemic complex 4 was submitted to X-ray analysis9 to con®rm the proposed
tricyclic structure. As it can be seen from Fig. 1, the Cr(CO)3 unit lies on the opposite side to the
C-3 and C-4 hydrogens of the b-lactam ring.

P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
1929
Figure 1. ORTOPEDII plot of 4. Ellipsoids are at 50% of probability level; H atoms not to scale
Such a con®guration is quite surprising on the basis of the accepted stereochemical model10 for
the chiral ortho-substituted benzaldehyde chromium complexes and for the imines4 in the [2+2]
cycloaddition. In fact, following the model, the complexed azetidinones 2 and 3 (Scheme 2, path
A) should have the Cr(CO)3 unit on the same side of the two hydrogens of the b-lactam ring when
the ¯uorine atom is placed in front of the nucleophilic oxygen anion at the moment of tricyclic
ring closure, giving rise therefore to cisoid 4 (cisoid with respect to the two hydrogens of the
b-lactam ring versus the Cr(CO)3 unit). We obtained instead transoid 4 that could arise either
from the b-lactam 3b,b (derived from the unfavourable conformation of the imine 1B) (Scheme 2,
path B), or from an inversion of the ring functions versus the Cr(CO)3 unit during the ring clo-
sure of the b-lactam 3a,a (Scheme 2, path D)
The absolute con®guration of the new ortho-¯uoro-substituted b-lactam (^)-2, obtained from
the enantiomerically pure (^)-(1R) imine 1, proves the validity of the stereochemical model. In
fact from the conformer 1A (the preferred one following the stereochemical model) the expected
b-lactam 2 is a,a with the absolute con®guration (3R,4R) for the complexed and (3R,4S) for the
decomplexed one (Scheme 2, path A). On the contrary, the b-lactam 2 is b,b (Scheme 2, path B)
with the absolute con®guration (3S,4S) from the conformer 1B. Therefore the same sequence of
reactions was repeated starting from the enantiomerically pure (^)-(1R) imine 1 (see Scheme 1).
The diastereomeric ratio found for the racemic 2 (d.e.>98%) was con®rmed by decomplexing a
sample of optically active (^)-2 by means of air and sunlight to the corresponding N-(4-methoxy-
1
phenyl)-3-acetoxy-4-(2-¯uorophenyl)-azetidin-2-one (+)-2a which showed, by H NMR in the
presence of Eu(hfc)3, an e.e. higher than 98%.
The determination of the absolute con®guration of (+)-2a relies upon enzymatic hydrolysis
experiments and the Cotton11 e€ect. It is known that Pseudomonas lipase preferentially hydro-
lyzes the (3S,4R) enantiomer of 3-acetoxy-1,4-diphenyl b-lactam to the 3-hydroxy derivative,12
con®rmed as well by us for a series of 4-(ortho-substituted aryl) b-lactam.5 Racemic 2a (Scheme 1),
submitted to kinetic resolution, gave rise to (+)-(3R,4S)-3-acetoxy derivative and (^)-(3S,4R)-
3-hydroxy derivative, supporting the (3R,4R) absolute con®guration for complexed (^)-2.

1930
P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
Scheme 2.
The positive Cotton e€ect in the CD curve11 of (+)-2a is in good agreement with the (3R,4S)
con®guration ®nally con®rming the validity of the adopted model.
After removal of the acetoxy group by means of hydrazine in methanolic solution, (+)-3 was
1
cyclized to (^)-4 and decomplexed to (^)-5. The e.e. of tricyclic (^)-5, determined by H NMR,
was higher than 98%. Therefore, the step (+)-3!(^)-4 was enantioselective but involved the
inversion of the relative con®guration between the Cr(CO)3 group and the C3±C4 hydrogens,
going from (+)-3a,a to transoid (^)-4 (Scheme 2, path D).

P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
1931
Two reasonable mechanistic pathways leading to transoid 4 are hypothesized: (a) the aromatic
nucleophilic substitution follows a tele±meta mechanism13 rather than an ipso mechanism, involving
the inversion of the stereochemistry of the complexed arene; (b) the oxy-anion generated from
base treatment of 3a,a (3R,4R) promotes an unusual ring opening across the C3±C4 bond to a
benzylic carbanion (stabilized by Cr(CO)3 unit) that regenerates the azetidinone ring by attack
from the Si-face of the carbonyl group producing the enantiomeric hydroxy derivative 3b,b
(3S,4S) (see Scheme 3).
Scheme 3.
As regards to pathway (a), we have never found results di€erent from the ipso-substitution
mechanism14 for the intermolecular aromatic nucleophilic substitution. Nevertheless, we con-
sidered it advisable to gain deeper insight about the plausibility of a tele±meta mechanism13 in the
case of sterically hindered intramolecular substitution.
Therefore, we submitted the racemic cis 6b (Scheme 4), synthesized in the usual way, to cyclization;
no tricyclic product was detected even at longer reaction times. However, by changing the solvent
from DME to DMF a 25% of trans 3-hydroxy derivative was obtained besides the recovery of
starting cis 6b. Such an isomerization may be due to azetidinone ring opening, similar to the one
shown in Scheme 3, which could be favoured by structure strain. PM315 geometry calculation for
a series of 3-hydroxy b-lactams (Fig. 2), such as 4-(2-¯uorophenyl) A, 4-[2-¯uoro-(Z6-tricarbonyl-
chromium)phenyl] B and 4-(2-¯uoro-4-nitrophenyl) C and their corresponding 3-oxy-anions was
performed.16 These calculations indicate that the C3±C4 bond length does not change in the series
A±C, but strongly increases going from A1 to B1±C1. These observations could support the
hypothesis that the oxy-anion formation promotes the unusual cleavage of the C3±C4 bond
when the negative charge in the benzylic position may be stabilized due to the electron-
withdrawing e€ect of the Cr(CO)3 group, similar to the nitro group in the para position of the
arene ring.
As a further support to the unusual C3±C4 bond breaking, racemic 7 was submitted to the
lipase kinetic resolution (Scheme 5). At approximately 50% conversion, the (3R)-acetoxy-(4S)-
(4-nitrophenyl) derivative 7 (‰ꢀŠD=+34.9, c 1.2, CHCl3, e.e. 49%) and a mixture of cis and

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P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
Scheme 4.
trans 3-hydroxy derivative (7a and 7b) were recovered. After separation, both 7a and 7b show
‰ꢀŠDꢁ0; the racemization of the cis isomer must involve the double epimerization of both C3±C4
centres of the b-lactam, which can be explained only by ring opening.
Scheme 5.
It is not surprising that during the ring closure (from 3!4, Scheme 1) no trans isomer was
detected, but, in contrast to the NO2 group in 7, the Cr(CO)3 unit, bonded to the ortho-
substituted arene, sterically hinders the formation of the trans isomer and directs stereoselectively
the subsequent attack of benzylic carbanion on the opposite side of the starting con®guration of
the 3-hydroxy anion. Therefore, the cis hydroxy derivative (Scheme 2), which undergoes the ring
closure to transoid 4, is the geometrically favoured 3b,b arising from 3a,a through C3±C4 bond
breaking (Scheme 2, path C). In fact, simulated geometries (PM3 level) show that the distance
from the oxygen anion and the ¯uorine atom is 5.12 A when the C3 and C4 hydrogens and
Cr(CO)3 are on the same side, and 4.87 A when they are on the opposite side, making
unfavourable the formation of tricyclic cisoid 4.
Therefore, we state that the tricyclic product (^)-5 (Scheme 1) has the C3 and C4 centres of the
azetidinone ring with absolute con®guration (1S,5R) opposite to the one of the precursor mono-
cyclic b-lactam (+)-3 (3R,4R).
Finally, to evaluate the ultimate scope of the procedure, the same reaction sequence outlined
in Scheme 1 was repeated starting from the ortho-chloro-substituted tricarbonylchromium
benzaldehyde, but the corresponding 3-hydroxy derivative does not undergo the cyclization, the
only material recovered at longer reaction times being the decomplexed substrate.

P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
1933
Figure 2.

1934
P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
3. Summary
A sample of 5 was submitted to microbiological screening to assess any activity as antibacterial
or b-lactamase inhibitor.
We would like to emphasize that chiral ortho-substituted arenetricarbonylchromium derivatives
are capable of controlling the absolute stereochemistry in the formation of the azetidinones and
in further cyclization when benzylic anions are involved, these substrates being useful auxiliary
tools for the diastereoselective synthesis of products with a potential biological activity. The
synthesis of the new tryciclic 5 in enantiopure form supports further extension of the above
method to additional compounds.
4. Experimental
All reactions were performed under a nitrogen atmosphere. Thermolysis with hexacarbonyl-
chromium(0) were carried out in a round-bottomed ¯ask, equipped with a Liebig air condenser
and a water condenser on top. All chemicals were used as obtained from commercial sources.
Column chromatography and TLC were carried out using, respectively, silica gel 60 and silica gel
60 F254 pre-coated plates. The melting points were measured using a Buchi 510 apparatus and are
uncorrected. The IR spectra were recorded using a 1725X FTIR spectrometer. NMR spectra
were recorded in CDCl3 using Varian XL 300, Bruker AC 300 and AMX 300 spectrometers.
Evaluation of enantiomeric excess was performed using Eu(hfc)3, (tris-[3-(hepta¯uoropropyl-
hydroxymethylene)-(+)-camphorato]europium(III) salt. The optical rotations were measured
using a Perkin±Elmer 241 polarimeter, with a 1 dm pathlength at 25ꢀC. The racemic compounds
were prepared as previously reported. The enantiomerically pure complexed benzaldehydes were
obtained by resolution of the corresponding racemic substrate using a known procedure.8
4.1. Preparation of (^)-tricarbonyl[N-(2-¯uorobenzylidene)-4-methoxyaniline]chromium 1
N-Methoxyaniline (284 mg, 2.31 mmol) was added under magnetic stirring to a solution of (^)-
(1R) 2-¯uorobenzaldehyde tricarbonylchromium {‰ꢀŠD=^1035 (c 0.102, CHCl3)} (600 mg, 2.31
mmol) in dry Et2O (20 ml) and absolute EtOH (20 ml). The mixture was maintained at room
temperature for 24 h, monitored by TLC (Et2O/petroleum ether 3/1). After ®ltration and
evaporation of the solvent under reduced pressure, the residue was dissolved in Et2O (30 ml) and
dried over Na2SO4. After ®ltration and evaporation, the red oil was crystallized by pentane (3±5
ml) and ®ltered. Yield 97%, orange solid, mp 114ꢀC (pentane). ‰ꢀŠD=^341 (c 0.24, CHCl3). ꢁ(max)
(Nujol) 1985, 1934, 1897, 1616 cm^1. 1H NMR (CDCl3) ꢂ 3.8 (s, 3H, OMe); 5.0 (dt, 1H, J=6.4, 2
Hz, arom. Cr(CO)3); 5.4 (t, 1H, J=6.2 Hz, arom. Cr(CO)3); 5.6 (m, 1H, arom. Cr(CO)3); 6.55 (m,
1H, arom. Cr(CO)3); 6.9±7.2 (AB system, 4H, arom.); 8.4 (s, 1H, CHˆN). Anal. calcd for
C17H12CrFNO4 (365.284): C, 55.90; H, 3.31; N, 3.83. Found C, 55.91; H, 3.32; N, 3.82.
4.2. Preparation of tricarbonyl[N-(4-methoxyphenyl)-3(R)-acetoxy-4(R)-(2-¯uorophenyl)azetidin-
2-one]chromium (^)-2
A solution of acetoxyacetyl chloride (0.41 ml, 3.82 mmol) in 5 ml of dry CH2Cl2 was carefully
added to a solution of (^)-(1R) 1 (400 mg, 1.09 mmol) and Et3N (0.91 ml, 6.53 mmol) in 8 ml of

P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
1935
dry CH2Cl2 cooled to 0ꢀC. The reaction was maintained for 6 h at 0ꢀC and overnight at room
temperature. The reaction was quenched with 10 ml of H2O and the organic layer dried over
Na2SO4. After evaporation of the solvent at reduced pressure, the remaining brown solid was
puri®ed by chromatographic column (silica gel, eluent Et2O/petroleum ether 3/1) The product was
recovered as pale yellow solid, yield 93%, mp 199ꢀC (dec.) (from petroleum ether); [ꢀ]D=^25.5 (c
0.133, CHCl3). ꢁ(max) (Nujol) 1975, 1880, 1744 cm^1. 1H NMR (CDCl3) ꢂ 1.9 (s, 3H, COMe); 3.8
(s, 3H, OMe); 4.7 (m, 1H, arom. Cr(CO)3); 5.22 (m, 1H, arom. Cr(CO)3); 5.6 (d, 1H, J=5 Hz, H4);
5.6±5.5 (m, 2H, arom. Cr(CO)3); 6.5 (d, 1H, J=5 Hz, H3); 7.0±7.5 (AB system, 4H, arom.). Anal.
calcd for C21H16CrFNO7 (465.36): C, 54.20; H, 3.47; N, 3.01. Found C, 54.18; H, 3.45; N, 2.99.
4.3. Preparation of tricarbonyl[N-(4-methoxyphenyl)-3(R)-hydroxy-4(R)-(2-¯uorophenyl)azetidin-
2-one]chromium (+)-3
A solution of hydrazine monohydrate (0.047 ml, 0.97 mmol) in MeOH (3 ml) was added
dropwise to a suspension of (^)-2 (300 mg, 0.644 mmol) in 20 ml of MeOH cooled at 0ꢀC. The
reaction mixture was then warmed to 40ꢀC until clear (about 2 h). The completion of the reaction
was tested by TLC (eluent Et2O/petroleum ether 1/1).The addition of water (20 ml) to the solution
after cooling at room temperature a€orded a yellow solid that was extracted with CH2Cl2 (3Â20
ml), dried over Na2SO4 and, after evaporation of the solvent, ®ltered by addition of petroleum
ether. Yield 85%, mp 184±185ꢀC (dec.); ‰ꢀŠD=+31.3 (c 0.068 CHCl3). ꢁ(max) (Nujol) 3267, 1969,
1
1918, 1731 cm^1. H NMR (CDCl3) ꢂ 3.1 (brs, 1H, OH); 3.8 (s, 3H, OMe); 4.8 (m, 1H, arom.
Cr(CO)3); 5.2±5.5 (m, 5H, arom. Cr(CO)3 and H3 and H4); 7.0±7.5 (AB system, 4H, arom.). Anal.
calcd for C19H14CrFNO6 (423.322): C, 53.91; H, 3.33; N, 3.31. Found C, 53.93; H, 3.34; N, 3.30.
4.4. Preparation of (^)-tricarbonyl[3,4-benzo-6-(4-methoxyphenyl)-2,6-oxazabicyclo[3.2.0]hept-
3-en-7-one]chromium 4
A solution of (+)-3 (200 mg, 0.472 mmol) in DME (10 ml) was added to a suspension of NaH
(0.519 mmol, oil suspension) in 8 ml of dry DME. The reaction was monitored by TLC (eluent
Et2O). When the reaction was complete (about 2 h), the mixture was diluted with water (20 ml)
and extracted with CH2Cl2 (3Â20 ml). After evaporation of the solvent under reduced pressure,
the residue was chromatographed (SiO2, eluent Et2O) and, together with small amounts of
complexed (36 mg) and uncomplexed (28 mg) starting 3-hydroxy derivative 3 and a mixture
of unidenti®ed products, the tricyclic (^)-4 was recovered in 50% yield as a single diastereoisomer.
Pale yellow solid, mp 205ꢀC (dec.) (from petroleum ether); [ꢀ]D=^204.8 (c 0.290, CHCl3). ꢁ(max)
1
(Nujol) 1958, 1889, 1751 cm^1. H NMR (CDCl3) ꢂ 3.8 (s, 3H, OMe); 4.58 (t, 1H, J=6.1 Hz,
arom. Cr(CO)3); 5.1 (d, 1H, J=6.6 Hz, arom. Cr(CO)3); 5.4 (d, 1H, J=4.6 Hz, H5); 5.5 (t, 1H,
J=6.6 Hz, arom. Cr(CO)3); 5.8 (d, 1H, J=4.6 Hz, H1); 6.0 (d, 1H, J=6.1 Hz, arom. Cr(CO)3);
6.9±7.4 (AB system, 4H, arom.); M+1=403. Anal. calcd for C19H13CrNO6 (403.316): C, 56.58; H,
3.25; N, 3.47. Found C, 56.63; H, 3.24; N, 3.45.
4.5. Preparation of (^)-3,4-benzo-6-(4-methoxyphenyl)-2,6-oxazabicyclo[3.2.0]hept-3-en-7-one 5
by decomplexation of (^)-4
A solution of (^)-4 (200 mg, 0.496 mmol) in 15 ml of CH2Cl2 was exposed to air and sunlight
for about 4±6 h (the reaction time was determined by TLC). The solvent was removed under

1936
P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
reduced pressure, the residue was taken up with Et2O and ®ltered over a pad of Celite to remove
the chromium salts. The ether solution was evaporated and the residue was crystallized by pet-
roleum ether. Yield 98%, white solid, mp 169ꢀC (from petroleum ether); ‰ꢀŠD=^65.7 (c 0.149,
CHCl3). ꢁ(max) (Nujol) 1734 cm^1. 1H NMR (CDCl3) ꢂ 3.8 (s, 3H, OMe); 5.65 (d, 1H, J=4.5 Hz,
H5); 5.8 (d, 1H, J=4.5 Hz, H1); 6.9 (m, 4H, arom.); 7.3 (m, 1H, arom.); 7.5 (m, 3H, arom.). Anal.
calcd for C16H13NO3 (267.288): C, 71.90; H, 4.90; N, 5.24. Found C, 71.89; H, 4.91; N, 5.23. E.e.
>98%.
4.6. Decomplexation of (^)-2 and (+)-3
The same procedure reported for the preparation of (^)-5 was used. Product (+)-2a: yield 97%,
white solid, mp 117ꢀC (from petroleum ether); ‰ꢀŠD=+26.3 (c 0.114, CHCl3). ꢁ(max) (Nujol) 1744
cm^1. 1H NMR (CDCl3) ꢂ 1.8 (s, 3H, Me); 3.8 (s, 3H, OMe); 5.68 (d, 1H, J=4.9 Hz, H3); 6.02 (d,
1H, J=4.9 Hz, H4); 6.8 (AB system, 2H, arom.); 7.1 (m, 2H, arom.); 7.25±7.4 (m, 4H, arom.).
Anal. calcd for C18H16FNO4 (329.331): C, 65.65; H, 4.90; N, 4.25. Found C, 65.70; H, 4.91; N,
4.23. E.e. >98%. Product (+)-3a: yield 92%, white solid, mp 196±197ꢀC (from petroleum ether).
‰ꢀŠD=+180 (c 0.1, CHCl3). ꢁ(max) (Nujol) 3351, 1729 cm^1. 1H NMR (CDCl3) ꢂ 2.5 (d, 1H, J=8.4
Hz, OH); 3.8 (s, 3H, OMe); 5.25 (dd, 1H, J=5.1 and 8.4 Hz, H3); 5.53 (d, 1H, J=5.1 Hz, H4);
6.85 (AB system, 2H, arom.); 7.1±7.4 (m, 6H, arom.). Anal. calcd for C16H14FNO3 (287.293): C,
66.89; H, 4.91; N, 4.88. Found C, 66.91; H, 4.90; N, 4.86.
4.7. Enzymatic kinetic resolution of N-(4-methoxyphenyl)-3-acetoxy-4-(2-¯uorophenyl)azetidin-
2-one (þ)-2a
To 200 mg of (þ)-2a suspended in 9 ml of 0.1 M phosphate bu€er solution (pH 7.5)ꢀand 1 ml of
acetonitrile, 200 mg of Lipase-P17 was added; the mixture was vigorously stirred at 37 C. After 24
h the reaction was quenched by extraction of the mixture with ethyl acetate (3Â20 ml).
Evaporation of the solvent a€orded quantitatively a mixture that was separated by chromatography
to give the 3-acetoxy derivative ‰ꢀŠD=+25.8 (c 0.12, CHCl3), e.e. 97% and the corresponding
3-hydroxy derivative ‰ꢀŠD=^182 (c 0.23, CHCl3).
4.8. Preparation of tricarbonyl[4-¯uorobenzaldehyde]chromium
The complexation was performed as described for the corresponding ortho-substituted benz-
aldehyde to give the complexed diethylacetal, yellow solid, mp 34ꢀC from pentane. ꢁmax (Nujol)
1
1974, 1892, 1102, 1056 cm^1. H NMR (CDCl3) ꢂ 1.3 (dt, 6H, J=7, 0.9 Hz, Me); 3.65 (m, 4H,
CH2); 5.15 (s, 1H, CH); 5.45 (dt, 2H, J=6.6, 1.02 Hz, arom. Cr(CO)3); 5.8 (dd, 2H, J=6.8, 3 Hz,
arom. Cr(CO)3). Anal. calcd for C14H15CrFO5 (334.268): C, 50.31; H, 4.52. Found C, 50.52;
H, 4.50. A solution of the complexed diethylacetal was dissolved in the minimum quantity of
dioxane and, under vigorous stirring, treated at room temperature with a 10% aqueous solution
of HCl. The colour of the solution changed from yellow to red; the progress was monitored by
TLC (petroleum ether/Et2O 3/1). A saturated solution of NaHCO3 was added until pH 7 and
then about 70% of the solvent was eliminated by reduced pressure and Et2O was added. The
solution was washed with water and dried over Na2SO4. After evaporation of the solvent, the
residue was chromatographed. Yield 26%, red solid, mp 89ꢀC (from petroleum ether). ꢁmax
(Nujol) 1975, 1885, 1682 cm^1. 1H NMR (CDCl3) ꢂ 5.4±6.0 (AB system, 4H, arom. Cr(CO)3), 9.4

P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
1937
(s, 1H, CHˆN). 19F NMR (CDCl3) ꢂ ^132.286. Anal. calcd for C10H5FCrO4 (260.144): C, 46.17;
H, 1.94. Found C, 46.22; H, 1.93.
4.9. Preparation of tricarbonyl[N-(4-¯uorobenzylidene)-4-methoxyaniline]chromium
N-Methoxyaniline (378 mg, 3.07 mmol) was added to a solution of 4-¯uorobenzaldehyde tri-
carbonylchromium (800 mg, 3.07 mmol) in dry Et2O (25 ml) and absolute EtOH (25 ml) under
magnetic stirring. The mixture was maintained at room temperature for about 24 h, monitored by
TLC (Et2O/petroleum ether 5/1). After evaporation of the solvent under reduced pressure, the
residue was dissolved in Et2O (35 ml) and dried over Na2SO4. Filtration and evaporation a€or-
ded a red oil that was made crystalline by pentane (3±5 ml). Yield 95%, orange solid, mp 116ꢀC
(from ether/pentane). ꢁmax (Nujol) 1970, 1893, 1622 cm^1. 1H NMR (CDCl3) ꢂ 3.9 (s, 3H, OMe);
5.6 (m, 2H, arom. Cr(CO)3); 6.1 (m, 2H, arom. Cr(CO)3); 6.9±7.1 (AB system, 4H, arom.); 7.9 (s,
1H, CHˆN). 19F NMR (CDCl3) ꢂ ^134.27. Anal. calcd for C17H12CrFNO4 (365.284): C, 55.90;
H, 3.31; N, 3.83. Found C, 55.92; H, 3.30; N, 3.84.
4.10. Preparation of tricarbonyl[N-(4-methoxyphenyl)-3-acetoxy-4-(4-¯uorophenyl)azetidin-2-one]-
chromium (þ)-6a
A solution of acetoxyacetyl chloride (0.21 ml, 1.95 mmol) in 5 ml of dry CH2Cl2 was carefully
added to a solution of tricarbonyl[N-(4-¯uorobenzylidene)-4-methoxyaniline]chromium (200 mg,
0.55 mmol) and Et3N (0.35 ml, 2.5 mmol) in 8 ml of dry CH2Cl2 cooled to 0ꢀC. The reaction was
allowed to warm at room temperature and maintained for 6 h (TLC Et2O). The reaction was
quenched with 30 ml of saturated NH4Cl, extracted with CH2Cl2 (3Â25 ml) and the organic solvent
was dried over Na2SO4. After evaporation of the solvent at reduced pressure, the remaining
brown solid was puri®ed by column chromatography (silica gel, eluent Et2O/petroleum ether 4/1).
The product was recovered in 96% yield as pale yellow solid, mp 116ꢀC (dec.) (from petroleum
1
ether). ꢁmax (Nujol) 1972, 1898, 1751 cm^1. H NMR (CDCl3) ꢂ 1.9 (s, 3H, COMe); 3.8 (s, 3H,
OMe); 5.1 (d, 1H, J=4.9 Hz); 5.2 (dt, 2H, J=4.4, 1.8 Hz, arom. Cr(CO)3); 5.3 (dt, 2H, arom.
Cr(CO)3); 5.85 (d, 1H, J=4.9 Hz); 6.9±7.4 (AB system, 4H arom.). 19F NMR (CDCl3) ꢂ ^134.57.
Anal. calcd for C21H16CrFNO7 (465.36): C, 54.20; H, 3.47; N, 3.01. Found C, 54.25; H, 3.46; N, 3.00.
4.11. Preparation of tricarbonyl[N-(4-methoxyphenyl)-3-hydroxy-4-(4-¯uorophenyl)azetidin-2-one]-
chromium (þ)-6b
A solution of hydrazine monohydrate (0.069 ml, 1.44 mmol) in MeOH (4 ml) was added
dropwise to a suspension of 6a (440 mg, 0.945 mmol) in MeOH (30 ml) cooled at 0ꢀC. The
reaction mixture was then warmed at 40ꢀC until it became clear (about 3 h). The completion of
the reaction was tested by TLC (eluent Et2O/petroleum ether 5/1). The addition of water (30 ml)
to the solution cooled at room temperature a€orded a yellow solid, which was extracted with
CH2Cl2 (3Â20 ml), dried over Na2SO4 and, after evaporation of the solvent, ®ltered by addition
of petroleum ether. Yield 81%, yellow solid, mp 165ꢀC (dec.) (from CH2Cl2/pentane). ꢁmax (Nujol)
1
3295, 1965, 1894, 1723 cm^1. H NMR (CDCl3) ꢂ 3.1 (brs, 1H, OH); 3.7 ( s, 3H, OMe); 4.9 (d,
1H, J=5 Hz); 5.1±5.2 (m, 2H, arom. Cr(CO)3); 5.3±5.4 (m, 2H, arom. Cr(CO)3); 5.5 (m, 1H,);
6.8±7.3 (AB system, 4H, arom.). 19F NMR (CDCl3) ꢂ ^134.669. Anal. calcd for C19H14CrFNO6
(423.322): C, 53.91; H, 3.33; N, 3.31. Found C, 53.94; H, 3.32; N, 3.30.

1938
P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
4.12. Reaction of 6b with NaH in DMF
NaH (0.566 mmol, oil suspension) was added to a solution of 6b (200 mg, 0.472 mmol) in 5 ml of
DMF, under vigorous stirring. The reaction was monitored by TLC (eluent Et2O). After 5 h, the
mixture was diluted with water (20 ml) and extracted with CH2Cl2 (3Â20 ml). After evaporation
of the solvent under reduced pressure, the crude material (150 mg) was directly decomplexed by
exposing the solution in CH2Cl2 to air and sunlight for 4 h. The solvent was evaporated and the
residue was taken up with Et2O, ®ltered over Celite and evaporated. 1H NMR (CDCl3) show a 3:1
mixture of two diastereomeric 3-hydroxy derivatives. After chromatography (SiO2, eluent Et2O)
the pure cis and trans isomers were recovered. Product 6b cis decomplexed: 72 mg, white solid,
mp 146ꢀC (from pentane). ꢁmax (Nujol) 3339, 1723 cm^1. 1H NMR (CDCl3) ꢂ 3.08 (brs, 1H, OH); 3.74
(s, 3H, OMe); 5.16 (d, 1H, J=5.2 Hz); 5.24 (d, 1H, J=5.2 Hz); 6.7±7.1 (AB system, 4H, arom.);
7.3 (m, 4H, arom.). Anal. calcd for C16H14FNO3 (287.293): C, 66.89; H, 4.91; N, 4.88. Found C,
66.92; H, 4.88; N, 4.89. Product 6b trans decomplexed: 24.3 mg, white solid, mp 122ꢀC (from pentane).
ꢁ
max (Nujol) 3391, 1719 cm^1. 1H NMR (CDCl3) ꢂ 3.55 (brs, 1H, OH); 3.75 (s, 3H, OMe); 4.70 (d, 1H,
J=1.6 Hz); 4.81 (d, 1H, J=1.6 Hz); 6.75±7.1 (AB system, 4H, arom.); 7.2±7.4 (m, 4H, arom.).
Anal. calcd for C16H14FNO3 (287.293): C, 66.89; H, 4.91; N, 4.88. Found C, 66.90; H, 4.89; N, 4.86.
4.13. Preparation of N-(4-nitrobenzylidene)-4-methoxyaniline
4-Nitrobenzaldehyde (630 mg, 4.17 mmol) and 4-methoxyaniline (513 mg, 4.17 mmol) were
heated in EtOH (40 ml) under re¯ux for 25 min. The mixture was cooled and the yellow solid
®ltered. Yield 90%, mp 132ꢀC (from EtOH). ꢁmax (Nujol) 1568, 1504, 1338 cm^1. H NMR
1
(CDCl3) ꢂ 3.84 (s, 3H, OMe); 6.95±7.3 (AB system, 4H, arom.); 8.05±8.3 (AB system, 4H, arom.);
8.6 (s, 1H, CHˆN). Anal. calcd for C14H12N2O3 (256.264): C, 65.62; H, 4.72; N, 10.93. Found C,
65.68; H, 4.73; N, 10.95.
4.14. Preparation of N-(4-methoxyphenyl)-3-acetoxy-4-(4-nitrophenyl)azetidin-2-one (þ)-7
A solution of acetoxyacetyl chloride (0.42 ml, 3.9 mmol) in 10 ml of dry CH2Cl2 was carefully
added to a solution of tricarbonyl N-(4-nitrobenzylidene)-4-methoxyaniline (286 mg, 1.11 mmol)
and Et3N (0.7 ml, 5 mmol) in 10 ml of dry CH2Cl2 cooled to 0ꢀC. The reaction was allowed to
warm at room temperature and maintained for 3 h (TLC Et2O). The reaction was quenched with
30 ml of saturated NH4Cl, extracted with CH2Cl2 (3Â25 ml) and the organic solvent was dried
over Na2SO4. After evaporation of the solvent at reduced pressure, the remaining brown solid
was puri®ed by chromatographic column (silica gel, eluent Et2O). Yield 85%, pale yellow solid,
mp 165ꢀC (from Et2O). ꢁmax (Nujol) 1760, 1742, 1527, 1360 cm^1. H NMR (CDCl3) ꢂ 1.66 (s,
1
3H, COMe); 3.69 (s, 3H, OMe); 5.35 (d, 1H, J=4.9 Hz); 5.91 (d, 1H, J=4.9 Hz); 6.74±7.17 (AB
system, 4H, arom.); 7.38±8.17 (AB system, 4H, arom.). Anal. calcd for C18H16N2O6 (356.340): C,
60.67; H, 4.53; N, 7.86. Found C, 60.71; H, 4.52; N, 7.83.
4.15. Enzymatic kinetic resolution of N-(4-methoxyphenyl)-3-acetoxy-4-(4-nitrophenyl)azetidin-
2-one (þ)-7
To 300 mg of (þ)-7 suspended in 14 ml of 0.1 M phosphate bu€er solution (pH 7.5) and 1.5 ml
of acetonitrile, 300 mg of Lipase-P19 was added; the mixture was stirred vigorously at 37ꢀC. After

P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
1939
24 h the conversion was about 50%; the reaction was quenched by extraction of the mixture with
ethyl acetate (3Â30 ml). Evaporation of the solvent a€orded a mixture that was separated by
chromatography. The resolved 3-acetoxy derivative was recovered in 46% yield (139 mg) ‰ꢀŠD=+34.9
(c 1.2, CHCl3) and the two diastereomeric hydroxy derivatives trans and cis in 55:45 ratio. Product
(+)-7a cis: 44.4 mg; mp 154ꢀC (from petroleum ether). ꢁmax (Nujol) 3306, 1728 cm^1. H NMR
1
(CDCl3) ꢂ 3.75 (s, 3H, OMe); 4.0 (brs, 1H, OH); 5.30 ( d, 1H, J=5.2 Hz); 5.33 (d, 1H, J=5.2 Hz); 6.8±
7.2 (AB system, 4H, arom.); 7.5±8.2 (AB system, 4H, arom.). ‰ꢀŠD=ꢁ0 (c 0.62 CHCl3). Anal. calcd
for C16H14N2O5 (314.302): C, 61.14; H, 4.49; N, 8.91. Found C, 61.10; H, 4.50; N, 8.91. M+1=314.
Product 7b trans: 62 mg; mp 140ꢀC (from petroleum ether). ꢁmax (Nujol) 3223, 1732 cm^1. H
1
NMR (CDCl3) ꢂ 3.72 (s, 3H, OMe); 4.69 (d, 1H, J=1.5 Hz); 4.98 (d, 1H, J=1.5 Hz); 6.78±7.1
(AB system, 4H, arom.); 7.49±8.2 (AB system, 4H, arom.). ‰ꢀŠD=ꢁ0 (c 0.88, CHCl3). Anal. calcd for
C16H14N2O5 (314.302): C, 61.14; H, 4.49; N, 8.91. Found C, 61.17; H, 4.51; N, 8.92. M+1=314.
4.16. Preparation of tricarbonyl[N-(2-chlorobenzylidene)-4-methoxyaniline]chromium
N-Methoxyaniline (133 mg, 1.08 mmol) was added to a solution of (þ)-2-chlorobenzaldehyde
tricarbonylchromium (300 mg, 1.08 mmol) in dry Et2O (10 ml) and absolute EtOH (10 ml) under
magnetic stirring. The mixture was maintained at room temperature for about 24 h and monitored
by TLC (Et2O/petroleum ether 3/1). After evaporation of the solvents under reduced pressure, the
residue was dissolved in Et2O (30 ml) and dried over Na2SO4. Filtration and evaporation a€orded
a red oil that was made crystalline by pentane (3±5 ml) and then ®ltered. Yield 96%, orange solid,
ꢀ
1
mp 96 C (from pentane). H NMR (CDCl3) ꢂ 3.8 (s, 3H, OMe); 5.2 (t, 1H, J=7.2 Hz, arom.
Cr(CO)3); 5.45 (d, 1H, J=6.5 Hz, arom. Cr(CO)3); 5.55 (t, 1H, J=6.5 Hz, arom. Cr(CO)3); 6.55
(d, 1H, J=7.2 Hz, arom. Cr(CO)3); 6.9±7.25 (AB system, 4H, arom.); 8.5 (s, 1H, CHˆN). Anal.
calcd for C17H12ClCrNO4 (381.736): C, 53.49; H, 3.17; N, 3.67. Found C, 53.51; H, 3.16; N, 3.69.
4.17. Preparation of tricarbonyl[N-(4-methoxyphenyl)-3-acetoxy-4-(2-chlorophenyl)azetidin-2-one]-
chromium
A solution of acetoxyacetyl chloride (0.3 ml, 2.8 mmol) in 5 ml of dry CH2Cl2 was carefully
added to a solution of tricarbonyl[N-(4-chlorobenzylidene)-4-methoxyaniline]chromium (300 mg,
0.79 mmol) and Et3N (0.66 ml, 4.7 mmol) in 10 ml of dry CH2Cl2 cooled to 0ꢀC. The reaction was
allowed to warm at room temperature and maintained for 24 h (TLC Et2O). The reaction was
quenched with 30 ml of saturated NH4Cl, extracted with CH2Cl2 (3Â25 ml) and the organic sol-
vent was dried over Na2SO4. After evaporation of the solvent at reduced pressure, the remaining
brown solid was puri®ed by chromatographic column (silica gel, eluent Et2O/petroleum ether 3/1)
The product was recovered in 65% yield, pale yellow solid, mp 195ꢀC (from petroleum ether). 1H
NMR (CDCl3) ꢂ 1.9 (s, 3H, Me); 3.8 (s, 3H, OMe); 4.98 (t, 1H, J=6.2 Hz, arom. Cr(CO)3); 5.38
(d, 1H, J=6.2 Hz, arom. Cr(CO)3); 5.42±5.55 (m, 2H, arom. Cr(CO)3); 5.65 (d, 1H, J=5.1 Hz);
6.25 (d, 1H, J=5.1 Hz); 7.0±7.5 (AB system, 4H, arom.). Anal. calcd for C21H16ClCrNO7
(481.812): C, 52.35; H, 3.35; N, 2.91. Found C, 52.34; H,3.36; N, 2.90.
4.18. Preparation of tricarbonyl[N-(4-methoxyphenyl)-3-hydroxy-4-(2-chlorophenyl)azetidin-2-one]-
chromium
A solution of hydrazine monohydrate (0.03 ml, 0.63 mmol) in MeOH (3 ml) was added drop-
wise to a suspension of 3-acetoxy derivative (200 mg, 0.42 mmol) in MeOH (20 ml) cooled at 0ꢀC.

1940
P. Del Buttero et al. / Tetrahedron: Asymmetry 11 (2000) 1927±1941
The reaction mixture was warmed to 40ꢀC and maintained until it became clear (about 3 h). The
completion of the reaction was tested by TLC (eluent Et2O/petroleum ether 3/1). The addition of
water (20 ml) to the solution cooled at room temperature a€orded a yellow solid that was
extracted with CH2Cl2 (3Â20 ml), dried over Na2SO4 and, after evaporation of the solvent,
1
®ltered by addition of petroleum ether. Yield 78%, pale yellow solid. H NMR (CDCl3) ꢂ 3.0
(brs, 1H, OH); 3.8 (s, 3H, OCH3), 5.1 (m, 2H, arom. Cr(CO)3); 5.4 (d, 1H, J=5.3 Hz), 5.6 (m, 2H,
arom. Cr(CO)3 and H4); 6.5 (d, 1H, J=7.1 Hz, arom. Cr(CO)3); 6.85±7.5 (AB system, 4H,
arom.). Anal. calcd for C19H14ClCrNO6 (439.774): C, 51.89; H, 3.21; N, 3.19. Found C, 51.88;
H, 3.20; N, 3.18.
Acknowledgements
Thanks are due to the Italian MURST (grant 40 and 60%) and CNR-Rome for ®nancial sup-
port, Prof. Stefano Maiorana and Prof. Antonio Papagni for helpful discussions and Dr. Nadia
Buonomo for preliminary experiments.
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c=16.0393(11) A, ꢀ=87.131(6), ꢃ=84.255(7), ꢄ=81.225(8) ꢀ, V=857.13(11) A3, Z=2, Dx=1.563 Mg m^3,
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5.1<2ꢆ<55ꢀ; 3953 independent (merging R=0.0090), of which 3525 with Io>2ꢇ(Io) were considered observed.
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®t=1.081; the ®nal map range was ^0.28<D ꢈ<0.26 eA^3. Data available from the Cambridge Crystallographic
Data Centre, deposition number CCDC 141259.
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17. Generously supplied by Amano Co.