The [2 + 2] Staudinger cycloadditive route to enantiopure azetidino[4,1-d][1,4]benzooxazepines

Article abstract of DOI:10.1016/j.tetasy.2004.06.037

The [2 + 2] Staudinger cycloaddition between the C=N double bond of 2,3-dihydrobenzoxazepines 2 and 6 and a series of acetyl chlorides gave the azetidino[4,1-d][1,4]benzo oxazepines 3 and 7, 8, respectively. In the case of enantiopure 6, the cycloaddition

Full text of DOI:10.1016/j.tetasy.2004.06.037

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2555–2559
The [2+2] Staudinger cycloadditive route to enantiopure
azetidino[4,1-d][1,4]benzooxazepines
a
b
b
Paola Del Buttero,a, Giorgio Molteni, Antonio Papagni and Luciano Miozzo
*
a
`
Universita degli Studi di Milano, Dipartimento di Chimica Organica e Industriale, Via Golgi 19, 20133 Milano, Italy
Universita degli Studi di Milano-Bicocca, Dipartimento di Scienze dei Materiali, Via Cozzi 53, 20125 Milano, Italy
b
`
Received 10 June 2004; accepted 29 June 2004
Available online 3 August 2004
Abstract—The [2+2] Staudinger cycloaddition between the C@N double bond of 2,3-dihydrobenzoxazepines 2 and 6 and a series of
acetyl chlorides gave the azetidino[4,1-d][1,4]benzo oxazepines 3 and 7, 8, respectively. In the case of enantiopure 6, the cycloaddi-
tion diastereoselectivity was markedly dependent from the substituent a to the imine.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
substitution of fluorine with ethanolamine, (ii) acidic
hydrolysis of the diethylacetal function restoring the
aldehyde group followed by spontaneous cyclisation
(Scheme 1).
Due to their usefulness in the treatment of bacterial
infections,1 2-azetidinone based antibiotics are of great
relevance both in industrial and academic fields. Much
effort has been devoted to the synthesis of new b-lactam
antibiotics with enhanced antibacterial activity,2 or fea-
turing good resistance towards b-lactamases and
dehydropeptidases.3
Subsequent treatment of 2 with acetoxy, phenoxy and
phthalimidoacetyl chloride in the presence of triethyl-
amine afforded the racemic trans-azetidino[4,1-d][1,4]-
benzoxazepines 3a–c in satisfactory yields. The structure
of 3 has been assigned unambiguously by analytical and
spectral data. The trans arrangement of the two hydro-
gens in the 3- and 4-positions of the azetidinone ring has
From this latter point of view, tricyclic b-lactams repre-
sent very promising candidates.4 In line with our recent
reports on the synthesis of tricyclic b-lactams,5 here we
describe a straightforward and convenient procedure
for preparing racemic and enantiopure azetidino[4,1-
d][1,4]benzoxazepine skeletons exploiting the [2+2]
Staudinger cycloaddition between the C@N double
bond of 2,3-dihydrobenzoxazepines and ketene deriva-
tives, generated in situ from a series of acetyl chlorides.
1
been deduced by H NMR from the vicinal scalar cou-
pling constant of 2.1Hz, which falls in the 2.1–2.8Hz
range typical for a trans reciprocal spatial arrangement
in azetidinone derivatives.6
The enantiomerically pure 6a–c were obtained starting
from commercially available (S)-(+)-2-aminopropanol,
(S)-(+)-phenylglycinol and (S)-(+)-2-amino-3-methyl-1-
butanol, respectively, following the same procedure
described for 2. Compounds 6a,b undergo [2+2] cyclo-
addition reaction with phenoxy and phthalimidoacetyl
chloride, respectively, giving a diastereoisomeric mixture
of 7a,b and 8a,b in about a 50:50 ratio (Scheme 2 and
Table 1). The diastereoisomeric mixture could be sepa-
rated by column chromatography over silica gel only
in the case of cycloadducts 7b and 8b and their enantio-
meric purity was checked by 1H NMR using of Eu(hfc)3
[tris(heptafluoropropyl hydroxymethylene-(+)camphor-
ato)europium-(III)] as chiral shift reagent. In both cases,
the enantiomeric excess (ee) was found to be over 98%.
2. Results and discussion
Preliminary experiments were carried out on the achiral
2,3-dihydrobenzoxazepine 2 aimed at optimising the
experimental conditions. Compound 2 was readily syn-
thesised in two steps starting from 2-fluoro-5-nitrobenz-
aldehyde
diethylacetal
by:
(i)
O-nucleophilic
*
Corresponding author. Fax: +39-02-50314115; e-mail: paola.
delbuttero@unimi.it
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.037

2556
P. Del Buttero et al. / Tetrahedron: Asymmetry 15 (2004) 2555–2559
OEt
OEt
NO2
NO2
NO2
OEt
N
OEt
HCl
NH2
OH
NaH
+
NH2
dioxane
DME
F
O
O
1
2
NH2
R
O
O
O
H
H
NO2
R
NO2
N
N
N2H4, EtOH, ∆
Cl
R= phtalimido
Et3N, CH2Cl2
O
O
4
3
O
N
a: R = AcO, b: R = PhO, c: R =
O
Scheme 1.
OEt
OEt
O2N
R1
O2N
O2N
R1
OEt
N
OEt
NH2
OH
HCl
dioxane
NaH
DME
+
NH2
F
O
O
R1
5
6
R2
R2
1
O
O
HB
O
HB
2
R2
O2N
R1
R1
HA
O2N
N
3
N
Cl
Et3N, CH2Cl2
8
+
7
HA
O
4
O
6
5
7
8
N2H4,
EtOH, ∆
b
NH2
O
H
O2N
N
R1
O
9
c
Entry
a
b
R1
R2
Me
PhO
Ph
iPr
Phthalimido
Phthalimido
Scheme 2.
Table 1. [2+2] Cycloadditions onto enantiopure 7 in dry dichloromethane
Entry
R1
R2
Product yield (%)a 7+8
Product ratiob 7:8
a
b
c
Me
Ph
PhO
Phthalimido
Phthalimido
47
64
59
55:45
50:50
100:0
i-Pr
a Cumulative yields.
b Deduced from 1H NMR spectroscopy.
The absolute configurations of the newly formed stereo-
centres on the cycloadducts 7b and 8b were assigned
unambiguously on the basis of NOESY experiments.
These showed NOE enhancements of the signals of
the hydrogens HA and HB, and this is possible only
for a reciprocal spatial arrangement depicted by the
formulae 8. The stereochemistry of these cycloadducts
has also been supported by computational calculation
of their energy minima conformations optimised at the
AM17 level. The computed distances between HA and
8
˚
HB (8a: 2.89A; 8b: 2.80A) are in good agreement with
˚
NOESY experiments. Conversely, the computed HA–HB

P. Del Buttero et al. / Tetrahedron: Asymmetry 15 (2004) 2555–2559
2557
distance for the diastereoisomers 7a and 7b were 4.05
˚
and 4.02A, respectively. These are too long for observ-
ing any NOE enhancements as confirmed by the absence
of cross-peaks between these hydrogens in NOESY
experiments.
2:3). After 3h the reaction is completed and, in order
to neutralise the sulfuric acid, quenched with triethyl-
amine, then taken up with water (20mL) and extracted
with diethylether (5·10mL). The organic layer was
dried over sodium sulfate and evaporated under reduced
pressure giving 2-fluoro-5-nitrobenzaldehyde diethyl-
acetal (0.69g, 95%) as yellow oil. IR (film) 1530,
The [2+2] cycloaddition between enantiopure 6c and
phthalimidoacetyl chloride afforded 7c as the sole dia-
stereoisomer in 59% yield. On the basis of NOESY
experiments, we were able to assign the (1R,1aR) config-
uration to the newly formed stereocentres on the azetid-
inone ring.
1350cmꢀ1 1H NMR (CDCl3) d 1.20 (dt, 6H, J 1.7,
;
7.0Hz), 3.5–3.7 (m, 4H), 5.70 (s, 1H), 7.1–8.5 (m, 3H);
19F NMR (CDCl3) d ꢀ108.5; MS m/z 243 (M+).
4.3. (2-Bis-ethoxyethyl-4-nitro)phenyl-2-aminoethylethers
1 and 5. General procedure
To this point, the above results deserve some comments.
The formation of cycloadducts 3, 7 and 8, which show
the trans arrangement of the azetidinone ring can be ac-
counted for by the accepted stereochemical model of the
Staudinger reaction between cis-imines and ketenes.9
Furthermore, as can be inferred from Table 1, the dia-
stereoselectivity outcome of [2+2] cycloadditions onto
enantiopure 6 was markedly dependent from the substit-
uent a to the C@N double bond. This behaviour could
be accounted by considering the steric encumbrance of
the isopropyl substituent (R1) towards the incoming
phthalimido ketene with respect to methyl or phenyl
substituents.
To a suspension of 60% (dispersion in mineral oil)
sodium hydride (0.24g, 5.9mmol) in dry ethylene glycol
dimethylether (15mL) the appropriate ethanolamine
(5.9mmol) was slowly added, then 2-fluoro-5-nitrobenz-
aldehyde diethylacetal (1.43g, 5.9mmol) was added and
the solution colour turned to orange/red. The reaction
was monitored by TLC (eluent: diethyl ether–light
petroleum 5:2). After 1–5h at room temperature, the
reaction was quenched with water (20mL) and extracted
with dichloromethane (3·10mL). The organic layer was
dried over sodium sulfate and evaporated under reduced
pressure giving crude (2-bis-ethoxyethyl-4-nitro)phenyl-
2-aminoethylethers 1 and 5a–c, which were used without
further purification.
3. Conclusion
4.3.1. Compound 1. (1.56g, 98%). Yellow oil; IR (Nu-
1
In conclusion, in order to functionalise further the pre-
pared cycloadducts, the phthalimido protecting group
in 3c and 7b has been removed giving the amino deriva-
tives 4 and enantiopure 9 in good overall yields.
jol) 3390, 1520, 1340, 1270cmꢀ1; H NMR (CDCl3) d
1.10 (t, J 7.0, 6H), 1.50 (br s, 2H), 3.05 (t, J 5.1, 2H),
3.4–3.6 (m, 4H), 4.05 (t, J 5.1, 2H), 5.65 (s, 1H), 6.8–
8.4 (m, 3H); MS m/z 270 (M+). Anal. Calcd for
C13H20N2O5: C, 54.92; H, 7.09; N, 9.85. Found: C,
54.90; H, 7.1; N, 9.77.
4. Experimental
4.1. General
4.3.2. Compound 5a (from (S)-(+)-2-amino-1-propa-
25
D
nol). (1.64g, 98%). Yellow oil; ½aꢁ ¼ þ7:1 (c 1.28,
CHCl3); IR (Nujol) 3350, 1510, 1340, 1275cmꢀ1
;
1H
Melting points were determined with a Buchi apparatus
¨
NMR (CDCl3) d 1.1–1.3 (m, 9H), 1.70 (br s, 2H), 3.7–
3.4 (m, 5H), 3.7–3.8 (m, 1H), 4.05 (dd, J 4.1, 8.9, 2H),
5.75 (s, 1H), 6.9–8.5 (d, J 2.9, 1H); MS m/z 284 (M+).
Anal. Calcd for C14H22N2O5: C, 56.36; H, 7.43; N,
9.39. Found: C, 56.34; H, 7.44; N, 9.37.
in open tubes and are uncorrected. IR spectra were re-
corded with a Perkin–Elmer 1725 X spectrophotometer.
Mass spectra were determined with a VG-70EQ appara-
tus. 1H NMR (300MHz) and 13C NMR (75MHz) spec-
tra were taken with a Bruker AC 300 or a Bruker AMX
300 instrument (in CDCl3 solutions at room tempera-
ture). Chemical shifts are given as ppm from tetrameth-
ylsilane 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 2s and a mixing time (d8) of 700ms (compound
7b,c) or 800ms (compound 8b) was used. Optical rota-
tions were recorded on a Perkin–Elmer 241 polarimeter
at the sodium D-line at 25ꢁC.
4.3.3. Compound 5b (from (S)-(+)-phenylglyci-
25
D
nol). (2.08g, 98%). Yellow oil; ½aꢁ ¼ þ25:6 (c 0.87,
CHCl3); IR (Nujol) 3380, 1520, 1340, 1270cmꢀ1
;
1H
NMR (CDCl3) d 1.2–1.3 (m, 6H), 1.90 (br s, 1H), 3.4–
3.6 (m, 4H), 4.10 (dd, J 8.6, 8.7, 1H), 4.20 (dd, J 8.7,
3.9, 1H), 4.5 (dd, J 8.6, 3.9, 1H), 6.9–8.5 (m, 8H);
MS m/z 346 (M+). Anal. Calcd for C19H24N2O5: C,
63.32; H, 6.71; N, 7.77. Found: C, 63.34; H, 6.7; N,
7.75.
4.2. 2-Fluoro-5-nitrobenzaldehyde diethylacetal
4.3.4. Compound 5c (from (S)-(+)-2-amino-3-methyl-1-
25
D
butanol). (1.80g, 98%). Yellow oil; ½aꢁ ¼ þ14:9 (c
To a stirred solution of 2-fluoro-5-nitrobenzaldehyde
(0.5g, 3.0mmol) in absolute ethanol (20mL) triethyl-
orthoformate (0.53mL, 3.2mmol) and two drops of
97% sulfuric acid were added. The reaction was moni-
tored by TLC (eluent: diethylether/light petroleum
0.89, CHCl3); IR (Nujol) 3390, 1519, 1340, 1270cmꢀ1
;
1H NMR (CDCl3) d 1.00 (d, J 6.8, 6H), 8.2–8.3 (m,
6H), 1.6 (br s, 2H), 1.7–1.8 (m, 1H), 3.0–3.1 (m, 1H),
3.5–3.6 (m, 4H), 3.9 (dd, J 8.9, 7.7, 1H), 4.2 (dd, J
8.9, 3.7, 1H), 5.8 (s, 1H), 6.9–8.5 (m, 3H); MS m/z

2558
P. Del Buttero et al. / Tetrahedron: Asymmetry 15 (2004) 2555–2559
312 (M+). Anal. Calcd for C16H26N2O5: C, 58.88;
H, 8.58; N, 8.64. Found: C, 58.87; H, 8.65; N,
8.65.
The appropriate acyl chloride (acetoxyacetyl chloride:
3.5mmol; phenoxyacetyl chloride 1.1mmol; phthalim-
idoacetyl chloride 6.0mmol) was slowly added. The mix-
ture was stirred at ꢀ5ꢁC for 30min, then it was allowed
to stand at room temperature for 2–4h. Dichlorometh-
ane (50mL) was added and the mixture was washed first
with brine (25mL) and then with water (30mL). The
organic layer was dried over sodium sulfate and evapo-
rated under reduced pressure giving crude 3, 7 and/or 8.
The residue was chromatographed on a silica gel column
under vacuo with ethyl acetate (3a,c) or diethylether (3b)
affording pure 3a–c.
4.4. 7-Nitro-2,3-dihydrobenzo[f][1,4]oxazepines 2 and
6a–c. General procedure
To a solution of the appropriate 1 or 5a–c (4.6mmol) in
dioxane (30mL), 37% aqueous hydrochloric acid was
added to pH4 until a white solid was formed. After
15–30min at room temperature the reaction mixture
was neutralised with 5% aqueous sodium hydrogencar-
bonate, the solution became clear and was stirred for
further 30–60min. Water (20mL) was added and the
4.5.1. Compound 3a. (0.11g, 36%). Mp 175–176ꢁC; IR
1
mixture
was
extracted
with
dichloromethane
(Nujol) 1750, 1515, 1340 cmꢀ1; H NMR (CDCl3) d
(3·50mL). The organic layer was dried over sodium
sulfate and evaporated under reduced pressure giving
crude 7-nitro-2,3-dihydrobenzo[f][1,4]oxazepines 2 and
6a–c.
2.20 (s, 3H), 3.4–3.5 (m, 1H), 4.0–4.1 (m, 2H), 4.4–4.5
(m, 1H), 4.90 (d, J 0.9, 1H), 5.6 (d, J 0.9, 1H), 7.1–8.6
(m, 3H); MS m/z 292 (M+). Anal. Calcd for
C13H12N2O6: C, 53.43; H, 4.14; N, 9.58. Found: C,
53.46; H, 4.16; N, 9.60.
In the case of compounds 2 and 6a the residue was chro-
matographed on a silica gel column with diethylether.
4.5.2. Compound 3b. (0.12g, 37%). Mp 132–133ꢁC; IR
(Nujol) 1770, 1520, 1345cmꢀ1; 1H NMR (CDCl3) d 3.40
(ddd, J 2.9, 5.2, 13.7, 1H), 4.20 (ddd, J 3.5, 8.3, 13.7,
1H), 4.33 (ddd, J 3.5, 5.2, 12.8, 1H), 4.40 (ddd, J 2.9,
8.2, 12.8, 1H), 5.10 (d, J 1.6, 1H), 5.15 (d, J 1.6, 1H),
6.9–8.1 (m, 8H); MS m/z 314 (M+). Anal. Calcd for
C17H14N2O5: C, 62.57; H, 4.32; N, 8.58. Found: C,
62.58; H, 4.36; N, 8.56.
4.4.1. Compound 2. (0.64g, 73%). Yellow solid; mp
105–106ꢁC (from diisopropyl ether); IR (Nujol) 1640,
1
1510, 1345cmꢀ1; H NMR (CDCl3) d 4.0–4.1 (m, 2H),
4.3–4.4 (m, 2H), 7.1–8.3 (m, 3H), 8.20 (s, 1H); MS m/z
192 (M+). Anal. Calcd for C9H8N2O3: C, 56.25; H,
4.20; N, 14.58. Found: C, 56.28; H, 4.19; N, 14.59.
4.4.2. Compound (3S)-6a. (0.57g, 60%). Yellow solid;
4.5.3. Compound 3c. (0.09g, 24%). Mp 210ꢁC; IR (Nu-
25
1
mp 116–117ꢁC (from diisopropylether); ½aꢁ ¼ ꢀ113:7
jol) 1770, 1720, 1520, 1345cmꢀ1; H NMR (CDCl3) d
D
1
(c 1.13, CHCl3); IR (Nujol) 1635, 1515, 1335cmꢀ1; H
NMR (CDCl3) d 1.30 (d, J 6.8, 3H), 4.0–4.1 (m, 2H),
4.1–4.2 (m, 1H), 7.0–8.3 (m, 3H), 8.10 (s, 1H); MS m/z
206 (M+). Anal. Calcd for C10H10N2O3: C, 58.25; H,
4.89; N, 13.58. Found: C, 56.28; H, 4.90; N, 13.59.
3.5–3.6 (m, 1H), 4.1–4.2 (m, 2H), 4.4–4.5 (m, 1H), 5.20
(d, J 2.4, 1H), 5.30 (d, J 2.4, 1H), 7.1–8.1 (m, 7H); MS
m/z 379 (M+). Anal. Calcd for C19H13N3O6: C, 60.16;
H, 3.45; N, 11.08. Found: C, 60.14; H, 3.46; N, 11.1.
4.5.4. Compounds 7a+8a. As 55:45 diastereomeric
25
D
4.4.3. Compound (3S)-6b. (1.1g, 90%). Yellow solid;
mixture (47%); mp 50–60ꢁC; ½aꢁ ¼ þ21 (c 1.01,
25
D
mp 130–132ꢁC (from light petroleum); ½aꢁ ¼ ꢀ25:0 (c
CDCl3); IR (Nujol) 1760, 1525, 1345cmꢀ1. Anal. Calcd
for C18H16N2O5: C, 63.52; H, 4.74; N, 8.23. Found: C,
63.54; H, 4.76; N, 8.21. Diastereoisomeric ratio was
1.13, CHCl3); IR (Nujol) 1650, 1510, 1335cmꢀ1
;
1H
NMR (CDCl3) d 4.20 (dd, J 12.2, 6.1, 1H), 4.55 (d, J
12.2, 1H), 5.0 (br s, 1H), 7.0–8.3 (m, 8H), 8.40 (s, 1H);
MS m/z 268 (M+). Anal. Calcd for C15H12N2O3: C,
67.16; H, 4.51; N, 10.44. Found: C, 67.18; H, 4.49; N,
10.46.
1
determined from methyl signals at H NMR (CDCl3)
d 1.65 (d, J 6.6, 3H), and 1.35 (d, J 6.6, 3H), whose
integral was 55:45, respectively. Other signals: 3.9–4.5
(m, 3H), 5.1–5.2 (m, 2H), 7.0–7.4 (m, 6H), 7.9–8.1 (m,
2H).
4.4.4. Compound (3S)-6c. (1.03g, 96%). Thick oil;
25
D
½aꢁ ¼ ꢀ53:4 (c 0.69, CHCl3); IR (Nujol) 1645, 1520,
4.5.5. Separation of pure diastereoisomers (1R,1aR,3S)-
7b and (1S,1aS,3S)-8b from the diastereoisomeric mix-
ture. The crude diastereoisomeric mixture was purified
firstly from all by-products by column chromatography
over silica gel using dichloromethane–ethyl acetate 9:1
as eluent, then the two diastereoisomers of 7b and 8b
separated by another chromatography on a silica gel
column eluent: diethylether–light petroleum 7:3.
1340, 1265cmꢀ1; H NMR (CDCl3) 0.9–1.0 (m, 6H),
1.8–1.9 (m, 1H), 3.5–3.6 (m, 1H), 4.1 (dd, J 12.1, 5.1,
1H), 4.35 (d, J 12.1, 1H), 7.05–8.3 (m, 3H); MS m/z
234 (M+). Anal. Calcd for C12H14N2O3: C, 61.53; H,
6.02; N, 11.96. Found: C, 61.58; H, 6.0; N, 11.94. Com-
pound 6c was used without further purification.
1
4.5. Azetidino[4,1-d][1,4]benzoxazepines 3 and 7, 8.
General procedure
4.5.6. Compound (1R,1aR,3S)-7b. (0.15g, 32%). White
25
D
solid; mp 220ꢁC; ½aꢁ ¼ ꢀ108:0 (c 0.70, CHCl3); IR
A solution of 7-nitro-2,3-dihydrobenzo[f][1,4]oxazepine
2 or 6a–c (1.0mmol) and triethylamine (20% molar ex-
cess with respect to acyl chloride) in dry dichlorometh-
ane (15mL) was cooled under nitrogen at ꢀ5/ꢀ10ꢁC.
(Nujol) 1775, 1715, 1515, 1345cmꢀ1
;
1H NMR
(CDCl3) d 4.3–4.4 (m, 2H), 5.28 (d, J 2.3, 1H), 5.30
(dd, J 4.15, 9.7, 1H), 5.70 (d, J 2.3, 1H), 7.1–8.1 (m,
12H); MS m/z 455 (M+). Anal. Calcd for C25H17N3O6:

P. Del Buttero et al. / Tetrahedron: Asymmetry 15 (2004) 2555–2559
2559
C, 65.93; H, 3.76; N, 9.23. Found: C, 65.94; H, 3.76; N,
9.21. Ee >96%.
4.6.2. Compound (1R,1aR,3S)-9. (54mg, 60%). Yellow
25
D
solid; mp 189–190ꢁC; ½aꢁ ¼ ꢀ90:0 (c 0.57, CHCl3);
IR (Nujol) 3360, 1760, 1510, 1350cmꢀ1
;
1H NMR
4.5.7. Compound (1S,1aS,3S)-8b. (0.15g, 32%). White
(CDCl3) d 2.0 (br s, 2H); 4.0 (s, 1H); 4.1–4.2 (m, 1H);
4.3–4.4 (m, 1H); 4.80 (s, 1H); 4.15 (d, J 4.3, 1H); 5.3
(d, J 4.3, 1H); 7.1–8.1 (m, 8H). Anal. Calcd for
C17H15N3O4: C, 62.76; H, 4.65; N, 12.92. Found: C,
62.78; H, 4.64; N, 12.90.
25
D
solid; mp 208–210ꢁC; ½aꢁ ¼ þ354:6 (c 0.80, CHCl3);
IR (Nujol) 1775, 1725, 1510, 1340cmꢀ1
;
1H NMR
(CDCl3) d 4.25 (dd, J 13.0, 3.0, 1H), 4.77 (dd, J 2.7,
13.0, 1H), 5.05 (t, J 2.4, 1H), 5.50 (d, J 2.6, 1H), 5.55
(d, J 2.6, 1H), 7.1–8.1 (m, 12H); MS m/z 455 (M+). Anal.
Calcd for C25H17N3O6: C, 65.93; H, 3.76; N, 9.23.
Found: C, 65.96; H, 3.74; N, 9.24. Ee >96%.
Acknowledgements
4.5.8. Compound (1R,1aR,3S)-7c. (0.25g, 59%). After
column purification collected as white solid; mp 123–
Thanks are due to MURST and CNR for financial sup-
port. We thank the NMR technician Dr. Lara De Ben-
assuti, University of Milan, for NOESY experiments.
25
124ꢁC; ½aꢁ ¼ ꢀ221:3 (c 1.06, CHCl3); IR (Nujol)
D
1
1765, 1720, 1520, 1390, 1235cmꢀ1; H NMR (CDCl3)
d 1.20 (d, J 6.8, 3H), 1.25 (d, J 6.7, 3H), 2.10–2.15 (m,
1H), 4.0–4.1 (m, 1H), 4.20 (d, J 6.1, 2H), 5.15 (d, J
2.1, 1H), 5.25 (d, J 2.1, 1H), 7.0–8.0 (m, 7H); MS m/z
421 (M+). Anal. Calcd for C22H19N3O6: C, 62.70; H,
4.54; N, 9.97. Found: C, 62.69; H, 4.52; N, 9.94.
Ee >96%.
References
1. Samarendra, C. I.; Maiti, N.; Micetich, R.; Daneshtalab,
M.; Atchison, K.; Phillips, O. A.; Kunugita, C. J. Antibiot.
1994, 47, 1030.
4.6. 1-Amino-2-oxo-8-nitro-1,3,4,9b-tetrahydro-azetid-
ino[4,1-d][1,4]benzoxazepine 4 and (+)-1(R)-amino-2-oxo-
3(S)-phenyl-8-nitro-1,3,4,9b(S)-tetrahydro-azetidino[4,1-
d][1,4] benzoxazepine 9
2. (a) The Chemistry of b-Lactams; Page, M. I., Ed.; Blackie
Academic & Professional: New York, 1992; (b) The Organic
Chemistry of b-Lactams; Georg, G. I., Ed.; VCH: New
York, 1993; (c) Sammes, P. G. Chem. Rev. 1976, 76,
113.
3. (a) Hanessian, S.; Reddy, B. Tetrahedron 1999, 55, 3427; (b)
Kanno, O.; Kawamoto, I. Tetrahedron 2000, 56,
5639.
4. Chemistry and Biology of b-Lactam Antibiotics; Morris, R.
B., Gorman, M., Eds.; Academic: New York, 1982.
5. (a) Del Buttero, P.; Baldoli, C.; Molteni, G.; Pilati, T.
Tetrahedron: Asymmetry 2000, 11, 1927; (b) Del Buttero,
P.; Molteni, G.; Papagni, A.; Pilati, T. Tetrahedron 2003,
59, 5259.
6. (a) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988,
29, 4253; (b) Palomo, C.; Arrieta, A.; Cossio, F. P.;
Aizpurna, J. M.; Mielgo, A.; Aurrekoetxea, N. Tetrahedron
Lett. 1990, 31, 6429.
7. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J.
P. J. Am. Chem. Soc. 1985, 107, 3902.
To a suspension of 3c or 7b (0.25mmol) in absolute eth-
anol (4mL) a solution of monohydrate hydrazine
(0.27mmol) in absolute ethanol (2mL) was slowly
added. The mixture was refluxed for 2.5h (TLC ethyl
acetate as eluent). Evaporation of the solvent gave solid,
which was chromatographed on silica gel column under
vacuo with dichloromethane–methanol 9:1 (in the case
of 3c) or ethyl acetate (in the case of 7b) giving pure 4
or enantiomerically pure 9.
4.6.1. Compound 4. (49mg, 70%). Yellow solid; mp
194–195ꢁC; IR (Nujol) 3370, 1730, 1520, 1345cmꢀ1; 1H
NMR (CDCl3) d 2.0 (br s, 2H), 3.3–3.4 (m, 1H), 4.0–
4.1 (m, 1H), 4.15 (d, J 2.4, 1H), 4.35–4.40 (m, 1H), 4.60
(d, J 2.4, 1H), 7.1–8.1 (m, 3H); MS m/z 281 (M+). Anal.
Calcd for C11H11N3O6: C, 53.01; H, 4.45; N, 16.86.
Found: C, 63.05; H, 4.44; N, 16.84.
8. As implemented in the Hyperchem 7.04 Professional
package of programs. Hypercube Inc. 2002.
9. Hegedus, L. S.; Montgomery, J.; Narukawa, Y.; Snustad,
D. C. J. Am. Chem. Soc. 1991, 113, 5784.