Nitrilimine cycloaddition onto 2-azetidinones bearing alkenyl dipolarophile(s)

Article abstract of DOI:10.1016/j.tet.2005.01.016

Silver acetate-promoted nitrilimines cycloaddition onto 3(R*)-phenyl-4(R*)-cinnamoyl-2-azetidinone 1 were highly stereoselective giving 4-(4,5-dihydropyrazol-5-yl) carbonyl-2-azetidinones 5 as the major products and regioisomeric 4-(4,5-dihydropyrazol-4-yl) carbonyl-2-azetidinones 6 as the minor one. When the same protocol was applied to the novel 3(R*)-phenyl-4(S*)-(4-benzoyl-E,E-1,3-butadienyl)-2- azetidinone 2 it resulted in site- and regioselective but not stereoselective cycloaddition, involving the formation of the four cycloadducts 10-13.

Full text of DOI:10.1016/j.tet.2005.01.016

Tetrahedron 61 (2005) 2413–2419
Nitrilimine cycloaddition onto 2-azetidinones bearing
alkenyl dipolarophile(s)
a
b
Paola Del Buttero,a, Giorgio Molteni and Tullio Pilati
*
a
`
Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy
bConsiglio Nazionale delle Ricerche, Istituto di Scienze e Tecnologie Molecolari, Via Golgi 19, 20133 Milano, Italy
Received 29 September 2004; revised 25 November 2004; accepted 7 January 2005
Available online 28 January 2005
Abstract—Silver acetate-promoted nitrilimines cycloaddition onto 3(R*)-phenyl-4(R*)-cinnamoyl-2-azetidinone 1 were highly
stereoselective giving 4-(4,5-dihydropyrazol-5-yl) carbonyl-2-azetidinones 5 as the major products and regioisomeric 4-(4,5-
dihydropyrazol-4-yl) carbonyl-2-azetidinones 6 as the minor one. When the same protocol was applied to the novel 3(R*)-phenyl-4(S*)-
(4-benzoyl-E,E-1,3-butadienyl)-2-azetidinone 2 it resulted in site- and regioselective but not stereoselective cycloaddition, involving the
formation of the four cycloadducts 10–13.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
regio- and stereoselectivity outcome of this methodology,
we decided to investigate further the behaviour of 3(R*)-
phenyl-4(R*)-cinnamoyl-2-azetidinone 15 towards
nitrilimines and to undertake the study of the novel 3(R*)-
phenyl-4(S*)-(4-benzoyl-E,E-1,3-butadienyl)-2-azetidi-
none 2 as dipolarophile (Fig. 1).
Since the discovery of penicillin in 1928, 2-azetidinone-
based heterocycles have become one of the most widely
used class of drugs for the systematic treatment of bacterial
infections.1 Due to their relevance in both clinic and
economic fields, variously substituted 2-azetidinones rep-
resent a very attractive target for contemporary organic
synthesis.2 As a result, considerable efforts have been
concerned with the design of new b-lactam antibiotics
which cover a wide spectrum of antibacterial activity.3 This
scenario was further substantiated by the discovery that
b-lactamases caused resistance against some penicillins and
cephalosporins, thus stimulating the search for new drugs
which should display enhanced stability towards the
b-lactamases.4 In a recent communication,5 we presented
the first stereoselective synthesis of a 4-(4,5-dihydro-
pyrazol-5-yl)carbonyl-2-azetidinone and the regioisomeric
4-(4,5-dihydropyrazol-4-yl)carbonyl-2-azetidinone. We
were intrigued by the chance to incorporate in the same
molecule the 2-azetidinone and the pyrazole rings, the latter
being found in several compounds which display biological
activity as antinflammatory6 and anti-coagulating7 factors.
As a good way to bring together the above-mentioned
fragments we exploited nitrilimine 1,3-dipolar cyclo-
addition onto the 2-azetidinone bearing an ethylenic
dipolarophile bond. To gain better insight about the site-,
Figure 1.
2. Results and discussion
2.1. Nitrilimine cycloadditions to 3(R*)-phenyl-4(R*)-
cinnamoyl-2-azetidinone 1
The generation of nitrilimine intermediate 4 was accom-
plished in situ by treatment of the corresponding hydra-
zonoyl chloride 38 with an equimolecular amount of silver
acetate in dry dioxane at room temperature in the presence
of 15. Besides the recovery of some0quantity of unreacted 1,
regioisomeric cycloadducts (4R*,5 S*)-5 and (4R*,40R*)-6
were obtained (Scheme 1). Reaction times, overall product
yields and regioisomeric ratio data are summarised in
Table 1. Product separation was achieved by simple silica
Keywords: Nitrilimine cycloaddition; Alkenyl-2-azetidinones; Stereoselec-
tive synthesis; 4,5-Dihydropyrazoles.
* Corresponding author. Tel.: C39 0250314145; fax: C39 0250314139;
e-mail: paola.delbuttero@unimi.it
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.016

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P. Del Buttero et al. / Tetrahedron 61 (2005) 2413–2419
Scheme 1.
Table 1. Cycloadditions between hydrazonoyl chlorides 3 and azetidinone 1
Reactant
Time (h)
Product and yields (%)a
Product ratiob
1
5
6
5:6
3a
3b
30
100
15
5
56
71
14
14
80:20
83:17
a Isolation yields.
b Deduced from 1H NMR analysis of reaction crudes.
gel column chromatography, while analytical and spectro-
scopic data of the cycloadducts are in full agreement with
the structures depicted. As far as cycloaddition regio-
chemistry is concerned, it reflects that observed in the
reaction between nitrilimines and a,b-unsaturated
carbonyls.9 On the other hand, the stereochemical outcome
of the cycloaddition deserves some comments. Both major
product (4R*,50S*)-5 and minor product (4R*,40R*)-6 were
detected as single stereoisomers thus making the cyclo-
addition fully stereoselective. This fact can be understood
by close inspection of Dreiding stereomodels of 1, which
clearly shows that the phenyl ring in the 3-position of the
2-azetidinone moiety effectively hinders one of the two
diastereofaces of the alkenyl dipolarophile. It needs to be
added that the relative configurations of the newly-formed
stereocentres of major 5 and minor 6 is dependent upon the
conformation of 1. In our preceding paper5 we assumed that
the free interchange between the four possible confor-
mations of the cinnamoyl fragment in the 4-position of the
2-azetidinone ring of 1 is precluded by severe steric
repulsion (Fig. 2), and we concluded that only the syn
s-cis conformation should be the reasonable candidate
describing the ground state conformation of 1. Here, these
assumptions find confirmation on the grounds of diffracto-
metric analysis of the novel major cycloadduct (4R*,50S*)-
5b (Fig. 3).10
Figure 3. ORTEP plot of (4R*,50S*)-5b. Ellipsoid at 20% of probability
level; H atoms not to scale. BlackZC,H; redZO; blueZN; brownZBr.
2.2. Nitrilimine cycloadditions to 3(R*)-phenyl-4(S*)-(4-
benzoyl-E,E-1,3-butadienyl)-2-azetidinone 2
In order to obtain the 2-azetidinone derivative 2, we
followed the three-step synthetic sequence outlined in the
Scheme 2. First, phenylglyoxal was submitted to Wittig
reaction in the presence of (triphenylphosphoranylidene)-
acetaldehyde. The resulting dienal 7, which was obtained as
the only isolable product, was readily converted to the imine
derivative 8 which was then reacted with phenylacetyl
chloride in the presence of triethylamine, thus following the
Staudinger [2C2] cycloaddition protocol. Compound 2 was
obtained as the major one (48%) and isolated in the
analytically pure state after chromatographic separation
from isomeric 3,4-trans 9 (12%). Next, 2-azetidinone 2 was
treated with hydrazonoyl chlorides 3 as described before
with 1. Since both of the conjugated olefins of 2 are suitable
position for dipolar attack, which can proceed with two
opposite orientations, both site-, regio- and stereoselectivity
phenomena can be involved in their cycloadditions. In fact,
Figure 2.

P. Del Buttero et al. / Tetrahedron 61 (2005) 2413–2419
2415
Scheme 2.
Scheme 3.
Table 2. Cycloadditions between hydrazonoyl chlorides 6 and azetidinone 2
Reactant
Time (h)
Product and yields (%)a
Product ratiob
10
11
12
13
10:11:12:13
6a
6b
48
190
31
25
31
25
13
9
13
9
35:35:15:15
37:37:13:13
a Isolation yields.
1
b Deduced from H NMR analysis of reaction crudes.
1,3-dipolar cycloaddition of nitrilimine 4 gave a complex
mixture of the four cycloadducts 10–13 (Scheme 3).
Reaction times, product yields and product ratio data are
given in Table 2. Structural assignment of cycloadducts
dipolar cycloadditions, it is possible envisage the formation
of up to four regio- and stereoisomeric cycloadducts. After
laborious chromatographic separation, the two major
products 10b and 11b were isolated in the pure state. The
latter products were submitted to oxidation with cerium (IV)
ammonium nitrate giving the same pyrazole derivative,
namely E-1-(azetidin-4-yl)-2-(pyrazol-4-yl)-ethylene 14
(Scheme 4). Following this chemical correlation experi-
ment, it can be argued that: (i) major cycloadducts 10 and 11
must be stereoisomers, and (ii) minor cycloadducts 12 and
13 also must be stereoisomers and regioisomeric with
1
10–-13 was somewhat laborious. H NMR spectroscopy of
crude reaction products showed the disappareance of the
signal due to the a-hydrogen to the benzoyl group of 2,
which resonates as a doublet at 6.91 d. This indicates that
only the activated alkenyl dipolarophile of 2 is involved in
cycloaddition, thus making the process fully site-selective.
To this point, due to the stereoconservativity typical of 1,3-

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P. Del Buttero et al. / Tetrahedron 61 (2005) 2413–2419
Scheme 4.
Figure 4. ORTEP plot of (4R*,50R*)-12b. Ellipsoid at 20% of probability
level; H atoms not to scale. BlackZC,H; redZO; blueZN; brownZBr.
Figure 6. AM1 optimised ground state conformations of the two major
cycloadducts: (a) (4R*,40R*)-10b; (b) (4R*,40S*)-11b.
respect to 10 and 11. Slow evaporation of a chloroformic
solution of 12b gave crystals suitable for X-ray diffracto-
metric analysis (Fig. 4)10 thus enabling us to the
unequivocal assignment of structures (4R*,50R*)-12 and
(4R*,50S*)-13 to the two minor cycloadducts. Structural
assignment of major 10 and 11 rely upon NOE experiment.
As can be seen from Figure 5, NOE enhancements between
HA–HB and HC–HD occurs in the case of (4R*,40R*)-10b,
while (4R*,40S*)-11b did not show any NOE enhancement.
This picture is consistent with the ground state confor-
mations of both major cycloadducts optimised at the AM111
Table 3. AM1 computed distances HA–HB, HC–HD of major cycloadducts
(4R*,40R*)-10b and (4R*,40S*)-11b
˚
Distance (A)
Product
HA–HB
HC–HD
(4R*,40R*)-10b
(4R*,40S*)-11b
2.56
3.12
2.87
3.13
level (Fig. 6),12 while HA–HB and HC–HD computed
distances are given in Table 3. As can be inferred from
Table 2, nitrilimine cycloaddition to 4-butadienyl-2-azeti-
dinone 2 occurs with a moderate degree of regioselectivity
but was not stereoselective. A comparison with the
behaviour of 4-cinnamoyl-2-azetidinone 1 suggest that
the distance between the reactive dipolarophile and the
2-azetidinone core is critical in determining cycloaddition
stereoselectivity. The phenyl ring in the 3-position of the
2-azetidinone ring of 2 cannot hinder one of the two
diastereofaces of the outer alkenyl dipolarophile thus
causing the lack of stereoselectivity.
Figure 5.

P. Del Buttero et al. / Tetrahedron 61 (2005) 2413–2419
2417
3. Conclusions
benzoyl-E,E-1,3-butadienyl)-2-azetidinone 9. A solution
of 8 (0.40 g, 1.4 mmol) and triethylamine (0.61 g,
6.0 mmol) in dry dichloromethane (25 mL) was cooled to
K5 8C. Phenylacetyl chloride (0.70 g, 4.5 mmol) in dry
dichloromethane (13 mL) was added under nitrogen
athmosphere and the resulting mixture was stirred and
cooled to 0 8C for 1 h, then at room temperature for 6 h. The
reaction was monitored by TLC (eluent: dichloromethane/
ethyl acetate 95:5). Brine (20 mL) was added and the
resulting mixture was extracted with dichloromethane
(2!20 mL). The organic layer was washed with water,
dried over sodium sulfate and evaporated under reduced
pressure giving a solid. The residue was chromatographed
on a silica gel column with t-butylmethyl ether/light
petroleum 3:2. First fractions gave 3,4-cis 2, further elution
gave isomeric 3,4-trans 9.
The site-, regio- and stereoselectivity involved in nitrilimine
1,3-dipolar cycloaddition to highly-functionalised 2-azetidi-
nones have been studied. Although regioselectivities obeys
the known rules dictated from FMO theory, stereo-
selectivies depend upon the length of the tether joining the
reactive dipolarophile to the 2-azetidinone core.
4. Experimental
4.1. General
Melting points were determined with a Bu¨chi apparatus in
open tubes and are uncorrected. IR spectra were recorded
with a Perkin–Elmer 1725! spectrophotometer. Mass
Compound 2. (0.27 g, 48%). IR (nujol) 1745, 1660 cmK1
;
1
spectra were determined with a VG-70EQ apparatus. H
1H NMR (CDCl3) d 3.80 (3H, s), 4.86 (1H, d, JZ6.0 Hz),
4.93 (1H, dd, JZ7.5, 6.0 Hz), 5.81 (1H, dd, JZ15.2,
7.5 Hz), 6.55 (1H, dd, JZ15.2, 10.7 Hz), 6.8–6.9 (2H, m),
6.92 (1H, d, JZ15.0 Hz), 7.14 (1H, dd, JZ15.0, 10.7 Hz),
7.4–7.9 (12H, m); MS m/z 409 (MC). Anal. Calcd for
C27H23NO3: C, 79.19; H, 5.66; N, 3.42. Found: C, 79.15; H,
5.63; N, 3.38.
NMR (300 MHz) spectra were taken with a Bruker AC 300
or a Bruker AMX 300 instrument (in CDCl3 solutions at
room temperature). Chemical shifts are given as ppm from
tetramethylsilane and J values are given in Hz. The NOESY
experiments were acquired with 1024 data points for 512
increments, without zero-filling. A relaxation delay (d1) of
2 s and a mixing time (d8) of 800 ms (compound 10b) or
700 ms (compound 11b) was used.
Compound 9. (70 mg, 12%). IR (nujol) 1745, 1660 cmK1
;
1H NMR (CDCl3) d 3.79 (3H, s), 4.26 (1H, d, JZ2.5 Hz),
4.54 (1H, dd, JZ7.7, 2.5 Hz), 6.42 (1H, dd, JZ15.2,
7.7 Hz), 6.69 (1H, dd, JZ15.2, 10.8 Hz), 6.8–6.9 (4H, m),
7.03 (1H, d, JZ15.0 Hz), 7.32 (1H, dd, JZ15.0, 10.8 Hz),
7.40–7.95 (10H, m); MS m/z 409 (MC). Anal. Calcd for
C27H23NO3: C, 79.19; H, 5.66; N, 3.42. Found: C, 79.26; H,
5.70; N, 3.47.
4.1.1. 6-Oxo-6-phenyl-hexa-2,4-E,E-dien-1-al 7. A sus-
pension of methyltriphenylphosphonium chloride (3.64 g,
10.7 mmol) in ethanol (16 mL) was warmed to 50 8C to
obtain a clear solution. Triethylamine (1.23 g, 12.2 mmol)
was added and the resulting dark solution was warmed to
50 8C for 0.5 h. The mixture was added dropwise to a stirred
solution of phenylglyoxal monohydrate (0.74 g, 4.9 mmol)
in ethanol (16 mL) under nitrogen athmosphere and then
warmed to 70 8C for 1.5 h. The reaction was monitored by
TLC (eluent: dichloromethane/ethyl acetate 95:5). Brine
(20 mL) was added and the resulting mixture was extracted
with dichloromethane (4!20 mL). The organic layer was
dried over sodium sulfate and evaporated under reduced
pressure giving 6-oxo-6-phenyl-hexa-2,4-E,E-dien-1-al 7
(0.41 g, 45%) as pale yellow powder, mp 86 8C (from
4.1.4. Nitrilimine cycloadditions to 3(R*)-phenyl-4(R*)-
cinnamoyl-2-azetidinone 1 and 3(R*)-phenyl-4(S*)-(4-
benzoyl-E,E-1,3-butadienyl)-2-azetidinone 2. To a
solution of 15 or 2 (1.0 mmol) and the appropriate
hydrazonoyl chloride 3 (2.0 mmol) in dry dioxane
(25 mL) was added silver acetate (0.17 g, 1.0 mmol). The
mixture was kept under vigorous stirring in the dark for 24 h
at room temperature. Hydrazonoyl chloride 3 (1.0 mmol)
and silver acetate (0.5 mmol) were added again, and the
mixture was stirred for further 24 h. The reaction was
monitored by TLC (eluent: light petroleum/ethyl acetate
65:35). The undissolved material was filtered off and
dichloromethane (40 mL) was added. The organic layer
was washed firstly with 5% aqueous sodium hydrogen-
carbonate, then with water (25 mL), dried over sodium
sulfate and evaporated under reduced pressure. The residue
was chromatographed on a silica gel column with
t-butylmethyl ether/light petroleum 65:35.
1
diisopropyl ether). IR (nujol) 1690, 1660, 1615 cmK1; H
NMR (CDCl3) d 6.51 (1H, dd, JZ15.3, 7.7 Hz), 7.32 (1H,
dd, JZ15.3, 7.9 Hz), 7.37 (1H, d, JZ15.0 Hz), 7.51 (1H,
dd, JZ15.0, 7.9 Hz), 7.5–7.8 (5H, m), 9.72 (1H, d, JZ
7.7 Hz); MS m/z 186 (MC). Anal. Calcd for C12H10O2: C,
77.40; H, 5.41. Found: C, 77.46; H, 5.46.
4.1.2. N-(4-Methoxyphenyl)-1-(5-oxo-5-phenyl-penta-
1,3-E,E-dienyl)methanimine 8. A solution of 4-methoxy-
aniline (0.30 g, 2.5 mmol) in ethanol (0.75 mL) was added
dropwise to 7 (0.46 g, 2.5 mmol) in ethanol (5.0 mL). The
mixture was stirred at room temperature for 5 min and the
solid material was filtered off giving 8 as yellow powder, mp
In the case of compounds 5 and 6 (from 2-azetidinone 1)
first fractions gave major 5, further elution gave minor 6.
108 8C (from ethanol). IR (nujol) 1650, 1590, 1560 cmK1
;
1H NMR (CDCl3) d 3.86 (3H, s), 6.9–7.1 (4H, m), 7.21 (1H,
d, JZ14.6 Hz), 7.25–7.60 (8H, m), 8.30 (1H, d, JZ8.1 Hz);
MS m/z 291 (MC). Anal. Calcd for C19H17NO2: C, 78.32;
H, 5.88; N, 4.81. Found: C, 78.27; H, 5.84; N, 4.75.
Compounds (4R*,50S*)-5b and (4R*,40R*)-6b were
obtained as previously described.5
Compound (4R*,50S*)-5b. (0.45 g, 71%) as yellow prisms,
mp 203 8C (from diisopropyl ether). IR (nujol) 1750,
4.1.3. 3(R*)-Phenyl-4(S*)-(4-benzoyl-E,EK1,3-buta-
dienyl)-2-azetidinone 2 and 3(R*)-phenyl-4(R*)-(4-
1
1735 cmK1; H NMR (CDCl3) d 3.67 (3H, s), 3.81 (3H,

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P. Del Buttero et al. / Tetrahedron 61 (2005) 2413–2419
1
s), 4.05 (1H, d, JZ3.3 Hz), 4.65 (1H, d, JZ3.3 Hz), 4.84
(1H, d, JZ6.3 Hz), 5.09 (1H, d, JZ6.3 Hz), 6.8–7.5 (18H,
m); MS m/z 638 (MC). Anal. Calcd for C34H28BrN3O5: C,
63.96; H, 4.42; N, 6.58. Found: C, 64.01; H, 4.45; N, 6.63.
1730 cmK1; H NMR (CDCl3) d 3.73 (6H, s), 4.50 (1H, d,
JZ4.9 Hz), 4.79 (1H, dd, JZ7.5, 4.9 Hz), 4.80–4.85 (2H,
m), 5.50 (1H, dd, JZ15.7, 3.8 Hz), 5.84 (1H, dd, JZ15.7,
7.5 Hz), 6.9–7.7 (18H, m); MS m/z 664 (MC). Anal. Calcd
for C36H30BrN3O5: C, 65.07; H, 4.55; N, 6.32. Found: C,
65.10; H, 4.51; N, 6.27.
Compound (4R*,40R*)-6b. (0.09 g, 14%) as pale yellow
powder, mp 182 8C (from diisopropyl ether). IR (nujol)
1
1745, 1730 cmK1; H NMR (CDCl3) d 3.73 (3H, s), 3.80
The mixture of compounds 11b and 12b was crystallised
with chloroform. Minor 12b was obtained as a crystalline
solid while the mother liquor contained major 11b.
(3H, s), 4.95 (1H, d, JZ6.6 Hz), 5.31 (1H, d, JZ4.1 Hz),
5.86 (1H, d, JZ6.6 Hz), 6.32 (1H, d, JZ4.1 Hz), 6.8–7.5
(18H, m); MS m/z 638 (MC). Anal. Calcd for
C34H28BrN3O5: C, 63.96; H, 4.42; N, 6.58. Found: C,
63.91; H, 4.46; N, 6.52.
Compound (4R*,40S*)-11b. (0.17 g, 25%). IR (nujol) 1745,
1730 cmK1; 1H NMR (CDCl3) d 3.74 (3H, s), 3.82 (3H, s),
3.86 (1H, dd, JZ8.5, 4.3 Hz), 4.85–4.90 (2H, m), 5.07 (1H,
d, JZ4.3 Hz), 5.45 (1H, dd, JZ15.7, 4.9 Hz), 6.02 (1H, dd,
JZ15.7, 8.5 Hz), 6.9–7.6 (18H, m); MS m/z 664 (MC).
Anal. Calcd for C36H30BrN3O5: C, 65.07; H, 4.55; N, 6.32.
Found: C, 65.14; H, 4.58; N, 6.37.
In the case of compounds 10a–13a (from 2-azetidinone 2),
first fractions gave major 10a, further elution gave a mixture
of 11a–13a.
Compound (4R*,40R*)-10a. (0.19 g, 31%). IR (nujol) 1740,
1730 cmK1; 1H NMR (CDCl3) d 2.29 (3H, s), 3.74 (3H, s),
3.82 (3H, s), 3.85 (1H, dd, JZ8.5, 4.4 Hz), 4.82–4.88 (2H,
m), 5.12 (1H, d, JZ4.4 Hz), 5.45 (1H, dd, JZ15.7, 5.0 Hz),
6.02 (1H, dd, JZ15.7, 8.5 Hz), 6.8–7.6 (18H, m); MS m/z
599 (MC). Anal. Calcd for C37H33N3O5: C, 74.11; H, 5.55;
N, 7.01. Found: C, 74.16; H, 5.58; N, 7.08.
Compound (4R*,50R*)-12b. (60 mg, 9%). Mp 186 8C (from
chloroform). IR (nujol) 1750, 1735 cmK1 1H NMR
;
(CDCl3) d 3.83 (6H, s), 4.58 (1H, d, JZ5.2 Hz), 4.75 (1H,
dd, JZ7.9, 5.2 Hz), 4.80–4.85 (2H, m), 5.48 (1H, dd, JZ
15.7, 3.5 Hz), 5.83 (1H, dd, JZ15.7, 7.9 Hz), 6.8–7.7 (18H,
m); MS m/z 664 (MC). Anal. Calcd for C36H30BrN3O5: C,
65.07; H, 4.55; N, 6.32. Found: C, 65.03; H, 4.55; N, 6.36.
The mixture of compounds 11a–13a was chromatographed
on a silica gel column with ethyl acetate/light petroleum 3:2.
First fractions gave major 11a, further elution gave a
mixture of minor 12a and 13a.
4.1.5. Cerium(IV) ammonium nitrate oxidation of major
cycloadducts 10b and 11b. A solution of 10b or 11b
(0.17 g, 0.26 mmol) in acetonitrile (15 mL) was cooled to
0 8C. Cerium(IV) ammonium nitrate (0.55 g, 1.0 mmol) in
water (8.0 mL) was added dropwise under vigorous stirring
and ice-cooling. The reaction was monitored by TLC
(eluent: light petroleum/ethyl acetate 3:2). After 2 h water
(15 mL) and saturated aqueous sodium dithionite (10 mL)
were added. The resulting mixture was extracted with ethyl
acetate (4!25 mL), the organic layer was washed with
water (2!25 mL) and dried over sodium sulfate. Evapor-
ation of the solvent under reduced pressure gave 14 as a dark
oil.
Compound (4R*,40S*)-11a. (0.19 g, 31%). IR (nujol) 1750,
1735 cmK1; 1H NMR (CDCl3) d 2.30 (3H, s), 3.72 (3H, s),
3.81 (3H, s), 3.89 (1H, dd, JZ8.0, 4.0 Hz), 4.80–4.86 (2H,
m), 5.19 (1H, d, JZ4.0 Hz), 5.50 (1H, dd, JZ15.6, 5.3 Hz),
6.01 (1H, dd, JZ15.6, 8.0 Hz), 6.7–7.8 (18H, m); MS m/z
599 (MC). Anal. Calcd for C37H33N3O5: C, 74.11; H, 5.55;
N, 7.01. Found: C, 74.08; H, 5.51; N, 6.94.
Compounds (4R*,50R*)-12a and (4R*,50S*)-13a (156 mg,
26%) were as 1:1 mixture on the basis of 1H NMR spectrum.
Diagnostic signals were at d 4.42 (1H, d, JZ5.0 Hz), first
minor diastereoisomer, and at d 4.57 (1H, d, JZ5.5 Hz),
second minor diastereoisomer.
Compound 14. (85 mg, 58%). IR (nujol) 1750, 1730 cmK1
;
1H NMR (CDCl3) d 3.99 (3H, s), 4.47 (1H, dd, JZ7.7,
5.2 Hz), 4.62 (1H, d, JZ5.2 Hz), 5.50 (1H, dd, JZ16.2,
7.7 Hz), 5.73 (1H, br s), 6.95 (1H, d, JZ16.2 Hz), 7.1–7.1
(14H, m); MS m/z 572 (MC). Anal. Calcd for
C29H22BrN3O4: C, 62.60; H, 3.99; N, 7.55. Found: C,
62.58; H, 3.97; N, 7.58.
In the case of compounds 10b–13b (from 2-azetidinone 2),
first fractions gave a mixture of major 10b and minor 13b,
further elution gave a mixture of major 11b and minor 12b.
The mixture of compounds 10b and 13b was chromato-
graphed on a silica gel column with dichloromethane/light
petroleum 9:1. First fractions gave major 10b, further
elution gave minor 13b.
Acknowledgements
Thanks are due to MURST and CNR for financial support.
We thank the NMR technician Dr. Lara De Benassuti,
University of Milan, for NOESY experiments.
Compound (4R*,40R*)-10b. (0.17 g, 25%). IR (nujol) 1745,
1730 cmK1; 1H NMR (CDCl3) d 3.81 (3H, s), 3.84 (3H, s),
3.87 (1H, dd, JZ7.9, 3.9 Hz), 4.82–4.88 (2H, m), 5.14 (1H,
d, JZ3.9 Hz), 5.50 (1H, dd, JZ15.7, 5.2 Hz), 6.01 (1H, dd,
JZ15.7, 7.9 Hz), 6.9–7.7 (18H, m); MS m/z 664 (MC).
Anal. Calcd for C36H30BrN3O5: C, 65.07; H, 4.55; N, 6.32.
Found: C, 65.12; H, 4.59; N, 6.39.
References and notes
Compound (4R*,50S*)-13b. (60 mg, 9%). IR (nujol) 1740,
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