Synthesis of a novel class of β-lactam derivatives of 1-aminophosphonates by staudinger ketene-imine [2+2]-cycloaddition reaction

Article abstract of DOI:10.1055/s-0030-1257889

A novel class of β-lactam derivatives of 1-aminophosphonates was synthesized by Staudinger [2+2] cycloaddition reaction of ketenes with imines derived from 1-aminophosphonates. Treatment of aromatic aldehydes with ammonia and diethyl phosphite followed by

Full text of DOI:10.1055/s-0030-1257889

3504
PAPER
Synthesis of a Novel Class of b-Lactam Derivatives of 1-Aminophosphonates
by Staudinger Ketene–Imine [2+2]-Cycloaddition Reaction
Babak Kaboudin,* Mohammad Bagher Afsharinezhad
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan 45137-66731, Iran
Fax +98(241)4214949; E-mail: kaboudin@iasbs.ac.ir
Received 31 May 2010; revised 15 June 2010
few papers have reported the synthesis of such com-
Abstract: A novel class of b-lactam derivatives of 1-aminophos-
pounds containing two functionalities in the same mole-
phonates was synthesized by Staudinger [2+2] cycloaddition reac-
tion of ketenes with imines derived from 1-aminophosphonates.
cule.19 The conjunction of two functionalities may afford
powerful biological activity.
Treatment of aromatic aldehydes with ammonia and diethyl phos-
phite followed by a reaction with ketenes, which are generated from
the appropriate acid chloride and a tertiary amine, gave a novel class
of b-lactam derivatives of 1-aminophosphonates. The major or, in
some cases, sole product of the cycloaddition is the cis-b-lactam.
H
H
H
N
H
N
H
H
N
R1
N
S
R
S
O
O
R2
O
Key words: 1-aminophosphonates, b-lactams, ketenes, imines,
[2+2]-cycloaddition reaction
O
CO2H
CO2H
penam
cephem
OH
O
OH
R2
H
H
S
H
H
N
a-Functionalized phosphonic acids have attracted grow-
ing attention because of their novel applications in indus-
try, agriculture and medicine, and as synthetic
intermediates.1–4 Among a-functionalized phosphonic
acids, 1-aminophosphonic acids are an important class of
compounds that exhibit a variety of interesting and useful
properties. 1-Aminophosphonic acids are considered to be
mimics of the corresponding 1-aminocarboxylic acids in
biological systems.5 Indeed, a number of potent antibiot-
ics,7 enzyme inhibitors,8 and pharmacological agents9 are
1-aminophosphonic acids or peptide analogues.
SR
SR1
N
O
CO2H
penem
CO2H
carbapenem
Figure 1
Recently, we have reported that the reaction of diethyl N-
(arylmethylene)-1-aminoaryl methylphosphonate with di-
ethyl phosphite in the presence of chlorotrimethylsilane or
acetyl chloride gives bis[1-diethoxyphosphorylal-
kyl]amine as the sole product (Scheme 1).20
The b-lactam skeleton is still attracting a lot of attention
due to its applications as antimicrobial agents and elastase
inhibitors.10 Due to the constant need for new drugs dis-
playing broader antibacterial activity, numerous penicillin
derivatives have been prepared and examined for antibac-
terial activity. Penams, carbapenems, cephalosporins, cla-
vulanic acids, and oxapenams constitute a variety of new
b-lactam-containing ring systems that are reported to
show antibacterial properties (Figure 1).11
R
R
O
O
TMSCl
CH2Cl2
R
P(OEt)
2 + H P(OEt)2
(EtO)2(O)P
N
P(O)(OEt)2
H
N
R
Scheme 1
A large number of synthetic methods for the preparation
of b-lactams have been developed.12 Of these methods,
the Staudinger reaction, in particular, has provided useful
and economical access to b-lactams, mainly due to the
ready availability of both Schiff bases and ketenes.13 The
key step in the Staudinger synthesis of b-lactams is the
[2+2] cycloaddition of ketenes, which are generated from
the appropriate acid chloride and a tertiary amine, with
imines.
We were interested in studying the synthesis of a novel
class of b-lactam derivatives of 1-aminophosphonates
through the Staudinger reaction of 1-iminophosphonates
with ketenes (Scheme 2).
R1
R2
O
O
base
O
R1
P(OEt)2
R2
+
N
P(OEt)2
Cl
O
N
In contrast to extensive studies on the synthesis of 1-ami-
R1
nophosphonates and b-lactam derivatives,14–18 relatively
R1
Scheme 2
SYNTHESIS 2010, No. 20, pp 3504–3508
x
x.
x
x
.
2
0
1
0
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1257889; Art ID: Z13910SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
b-Lactam Derivatives of 1-Aminophosphonates
3505
Treatment of diethyl N-(phenylmethylene)-1-aminophe- oxyphenyl) ethylphosphonate (1b) with a mixture of meth-
nyl methylphosphonate (1a), which was chosen as a mod- oxyacetyl chloride (2e) and triethylamine in toluene at
el compound and prepared by our previous reported room temperature afforded the corresponding b-lactam
method,21 with various acid chlorides was studied in the derivative 3g in 80% isolated yield (entry 6). Treatment of
presence of triethylamine in toluene, and the progress of 1b with phenoxyacetyl chloride (2f) in the presence of tri-
the reaction was monitored by TLC (Scheme 3).
ethylamine in toluene gave 3h in 72% isolated yield in
about 35% diastereomeric excess (entry 8). The reaction
of diethyl N-(4-fluorophenylmethylene)-1-amino (4-fluo-
rophenyl) ethylphosphonate (1c) with a mixture of meth-
oxyacetyl chloride (2e) and triethylamine in toluene at
room temperature, afforded the corresponding b-lactam
derivative 3i in 80% isolated yield (entry 9).
O
Ph
R
O
Ph
P(OEt)2
O
Et3N
O
+
R
N
P(OEt)2
toluene
N
Cl
Ph
Ph
1a
2
3
In summary, we have developed a novel synthesis of b-
lactam derivatives of 1-aminophosphonates by using the
Staudinger [2+2]-cycloaddition reaction of ketenes with
imines derived from 1-aminophosphonates. The major, or
sole, product of the cycloaddition is the cis-b-lactam. Us-
ing this method, a series of b-lactam derivatives of 1-ami-
nophosphonates was synthesized in good to excellent
yields. Some of the major advantages of this protocol are
the simple procedure, easy work-up, good yields, and cat-
alyst-free reaction conditions.
R = Me (2a), Et (2b), Ph (2c),
AcO (2d), MeO (2e)
Scheme 3
Treatment of 1a with propanoyl (2a), butanoyl (2b) and
phenylacetyl (2c) chlorides in the presence of triethyl-
amine in anhydrous toluene at room temperature for 24
hours, failed. When the reaction was carried out with ace-
toxy acetyl chloride (2d) in the presence of triethylamine
in anhydrous toluene for 12 hours at room temperature,
compound 3d was obtained in 64% isolated yield. The
structure of 3d was confirmed by NMR data and elemen-
tal analysis. In the 31P NMR spectrum, two singlet peaks
appeared at d = 18.43 and 18.81 ppm. The major, or sole,
product of the Staudinger [2+2]-cycloaddition reaction of
ketenes with imines was the cis-b-lactam.10 On the other
hand, due to the presence of the stereogenic center at the
a-position of the phosphonate moiety, compound 3d can
exist as two diastereoisomers. The diastereomeric excess
of 28% for 3d was calculated from the integrated areas of
the 31P NMR peaks. The 1H NMR spectrum contains two
sets of doublet peaks at d = 4.87 (JH–P = 21 Hz) and 5.13
(JH–P = 21.7 Hz) ppm, which corresponds to the hydrogen
CH-P in the two diastereoisomers. The 1H NMR spectrum
also contains two doublet peaks at d = 5.04 (J = 5 Hz) and
5.74 (J = 5 Hz) ppm, which corresponds to the cis hydro-
gens (g and d) in 3d for a single diastereoisomer. The sig-
nals for the cis hydrogens of the second diastereoisomer
showed two doublet peaks at d = 5.34 (J = 4.7 Hz) and
5.85 (J = 4.7 Hz) ppm. The 13C NMR spectrum exhibited
a two sets of doublet peaks at d = 54.1 (JC–P = 153.4 Hz)
All chemicals were commercial products and were either distilled or
recrystallized before use. NMR spectra were recorded with a 250
Bruker Avance instrument with chemical shifts (d) being reported
as ppm and couplings expressed in hertz; the chemical shift data are
given relative to CHCl3 (d = 7.26 ppm) for CDCl3 solution. For 13
C
NMR spectra, the chemical shifts in CDCl3 are recorded relative to
the CDCl3 resonance (d = 77.0 ppm). Silica gel column chromatog-
raphy was carried out with Merck Silica gel 60 (Merck No. 10184).
Merck Silica gel 60 F254 plates (No. 5744) were used for prepara-
tive TLC.
Synthesis of Diethyl N-(Arylmethylene)-1-aminoaryl Methyl-
phosphonate (1); General Procedure
Obtained according to our previously published article.21
The aldehyde (15 mmol) was added to NH4OH (30%, 15 mL) and
the solution was stirred for 5 h at reflux. During this time, a white
precipitate formed. The precipitate was removed by filtration and
dried. Diethyl phosphite (828 mg, 6 mmol) was added to this solid
and the resulting solution was stirred for 2–5 h at 70 °C. Chroma-
tography on silica gel (EtOAc–n-hexane, 5:5) gave the pure product
diethyl N-(arylmethylene)-1-aminoaryl methyl phosphonate 1 as a
colorless oil.21
and 56.2 (JC–P = 156.6 Hz) ppm for the two diastereoiso- Synthesis of Novel b-Lactam Derivatives of 1-Aminophospho-
nates (3); General Procedure
mers. The [2+2] cycloaddition reaction of 1a with meth-
oxyacetyl chloride (2e) in the presence of triethylamine
A solution of the acid chloride 2 (3.5 mmol) in anhydrous toluene
(10 mL) was slowly added to a solution of diethyl N-(arylmethyl-
converted the Schiff base 1a into the corresponding cis-b-
ene)-1-aminoaryl methylphosphonate 1 (1 mmol) and Et3N (4.5
lactam 3e at room temperature after 12 hours in good iso-
lated yield (80%) in about 20% diastereomeric excess.
The results are summarized in Table 1.
mmol) in anhydrous toluene (10 mL) at 0–5 °C. The reaction mix-
ture was then allowed to warm to r.t. and the reaction mixture was
stirred for 12–24 h. The reaction mixture washed with H2O (2 × 15
mL), sat. NaHCO3 (10 mL), and brine (10 mL). The organic layer
was dried over Na2SO4 and the organic solvent was removed by dis-
tillation under reduced pressure to give the crude product, which
was purified by column chromatography on silica gel (EtOAc–n-
hexane, 1:5→5:1) to give a diastereomeric mixture of b-lactams 3
Treatment of a range of derivatives of diethyl N-(aryl-
methylene)-1-aminoaryl methylphosphonates 1 with var-
ious acyl chlorides in toluene at room temperature were
examined (Table 1). As shown in Table 1, the reaction of
diethyl N-(4-methoxyphenylmethylene)-1-amino (4-meth- in 64–80% yields. All products gave satisfactory spectral data in ac-
cord with the assigned structures.
Synthesis 2010, No. 20, 3504–3508 © Thieme Stuttgart · New York

3506
B. Kaboudin, M. B. Afsharinezhad
PAPER
Table 1 Reaction of Diethyl N-(Arylmethylene)-1-aminoaryl Methylphosphonates 1 with Acyl Chlorides 2 in Toluene at Room Temperture
Entry Compound 1
Compound 2
Product 3
Time (h) Yield (%)a 31P NMR of 3
Ph
O
O
c
N
N
N
N
P(OEt)2
1
2
3
4
–
24
24
24
14
–
–
–
–
Cl
Ph
Ph
Ph
Ph
2a
1a
Ph
O
O
c
P(OEt)2
–
–
Et
Cl
2b
1a
Ph
O
O
c
P(OEt)2
–
–
Ph
Cl
2c
1a
Ph
Ph
AcO
O
O
O
18.43, 18.81
(28%)
P(OEt)2
64
N
O
P(OEt)2
AcO
Cl
Ph
2d
1a
3d
Ph
Ph
MeO
O
O
O
18.70, 19.11
(20%)
N
N
P(OEt)2
5
6
12
12
80
70
N
O
P(OEt)2
MeO
Cl
Ph
Ph
Ph
2e
1a
3e
Ph
Ph
PhO
O
O
O
18.59, 19.02
(4%)
P(OEt)2
N
O
P(OEt)2
PhO
Cl
Ph
2f
1a
3f
OMe
MeO
O
N
P(OEt)2
O
O
18.87, 19.37
(8%)
N
O
P(OEt)2
7
12
80
MeO
Cl
OMe
MeO
2e
1b
OMe
3g
OMe
O
N
PhO
P(OEt)2
O
O
18.83, 19.31
(35%)
N
O
P(OEt)2
8
12
72
PhO
Cl
OMe
MeO
2f
1b
OMe
3h
Synthesis 2010, No. 20, 3504–3508 © Thieme Stuttgart · New York

PAPER
b-Lactam Derivatives of 1-Aminophosphonates
3507
Table 1 Reaction of Diethyl N-(Arylmethylene)-1-aminoaryl Methylphosphonates 1 with Acyl Chlorides 2 in Toluene at Room Temperture
(continued)
Entry Compound 1
Compound 2
Product 3
Time (h) Yield (%)a 31P NMR of 3
F
O
N
MeO
P(OEt)2
O
O
18.33, 18.72
(32%)
N
P(OEt)2
9
14
80
MeO
O
Cl
F
F
2e
1c
F
3i
a Yields refers to the isolated pure products after column chromatography.
b 31P NMR d shifts and de in parentheses.
c Unknown mixture.
1-[(Diethoxyphosphoryl)phenylmethyl]-2-oxo-4-phenylazeti-
din-3-yl Acetate (3d)
Colorless oil; mixture of two diastereoisomers.
J = 21.3 Hz, 1 H), 5.05 (d, J = 4.7 Hz, 1 H), 5.16 (d, J = 21.5 Hz,
1 H), 5.33 (d, J = 4.2 Hz, 1 H), 5.36 (d, J = 4.5 Hz, 1 H), 5.46 (d,
J = 4.5 Hz, 1 H), 6.65 (d, J = 7.7 Hz, 4 H), 6.79 (t, J = 7.5 Hz, 2 H),
6.95–7.15 (m, 14 H), 7.15–7.27 (m, 4 H), 7.27–7.42 (m, 4 H), 7.44–
7.58 (m, 2 H).
1H NMR (CDCl3, 250 MHz): d = 1.02–1.45 (m, 12 H), 1.61 (s, 3 H),
1.63 (s, 3 H), 3.75–4.08 (m, 6 H), 4.10–4.30 (m, 2 H), 4.87 (d,
J = 21 Hz, 1 H), 5.04 (d, J = 5 Hz, 1 H), 5.13 (d, J = 21.7 Hz, 1 H),
5.34 (d, J = 4.7 Hz, 1 H), 5.74 (d, J = 5 Hz, 1 H), 5.85 (d,
J = 4.7 Hz, 1 H), 7.0–7.55 (m, 20 H).
13C NMR (CDCl3, 62.9 MHz): d = 16.1–16.5 (m), 19.8, 54.1 (d,
JP–C = 153.4 Hz), 56.2 (d, JP–C = 156.6 Hz), 62.6–63.7 (m), 127.7,
127.9, 128.3, 128.4–129.0 (m), 129.6–129.9 (m), 131.1, 131.9,
132.6, 164.9 (b-lactam CO), 169.0 (acetoxy CO).
13C NMR (CDCl3, 62.9 MHz): d = 16.1–16.6 (m), 53.9 (d, JP–C
=
154.1 Hz), 55.9 (d, JP–C = 156.6 Hz), 62.4 (d, JP–C = 7.5 Hz), 62.9
(d, JP–C = 7.6 Hz), 63.3 (d, JP–C = 6.9 Hz), 63.5 (d, JP–C = 6.9 Hz),
63.8 (d, JP–C = 2.5 Hz), 64.1, 115.5, 121.9, 127.6, 127.8, 128.2,
128.3, 128.4, 128.6, 128.7, 128.9, 129.1, 129.2, 129.7, 129.8, 131.2,
132.1, 132.9, 156.7, 165.7 (d, JP–C = 5.0 Hz), 165.8 (d, JP–C
=
5.0 Hz).
31P NMR (CDCl3, 101.25 MHz, H3PO4): d = 18.59 (52%), 19.02
(48%).
31P NMR (CDCl3, 101.25 MHz, H3PO4): d = 18.43 (major), 18.81
(minor).
Anal. Calcd for C26H28NO5P: C, 67.07; H, 6.07; N, 3.01. Found: C,
66.95; H, 6.15; N, 3.05.
Anal. Calcd for C22H26NO6P: C, 61.23; H, 6.08; N, 3.25. Found: C,
61.08; H, 6.15; N, 3.20.
Diethyl {(4-Methoxyphenyl)-[2-(4-methoxyphenyl)-3-methoxy-
4-oxoazetidin-1-yl]methyl}phosphonate (3g)
Colorless oil; mixture of two diastereoisomers.
Diethyl [(3-Methoxy-2-oxo-4-phenylazetidin-1-yl)phenylmeth-
yl]phosphonate (3e)
White powder; mixture of two diastereoisomers.
1H NMR (CDCl3, 250 MHz): d = 1.02–1.18 (m, 9 H), 1.25–1.37 (t,
J = 7 Hz, 3 H), 3.03 (s, 3 H), 3.05 (s, 3 H), 3.66 (s, 3 H), 3.71 (s,
3 H), 3.77 (s, 6 H), 3.80–4.02 (m, 6 H), 4.02–4.23 (m, 2 H), 4.53 (d,
J = 4.5 Hz, 1 H), 4.66 (dd, J = 3.2, 1.5 Hz, 1 H), 4.73 (d, J = 5 Hz,
1 H), 4.78 (d, J = 20.7 Hz, 1 H), 5.05 (d, J = 21.5 Hz, 1 H), 5.09 (s,
1 H), 6.53 (d, J = 8.7 Hz, 2 H), 6.64 (d, J = 8.7 Hz, 2 H), 6.77–6.9
(m, 4 H), 6.96–7.12 (m, 4 H), 7.24 (d, J = 8.7 Hz, 2 H), 7.37 (d,
J = 7.5 Hz, 2 H).
1H NMR (CDCl3, 250 MHz): d = 1.0–1.25 (m, 9 H), 1.33 (t,
J = 7 Hz, 3 H), 3.02 (s, 3 H), 3.03 (s, 3 H), 3.37–3.55 (q, J = 7 Hz,
1 H), 3.65 (q, J = 7 Hz, 1 H), 3.73–4.05 (m, 5 H), 4.05–4.25 (m,
1 H), 4.59 (d, J = 4.7 Hz, 1 H), 4.71 (d, J = 4.5 Hz, 1 H), 4.83 (d,
J = 4.7 Hz, 1 H), 4.85 (d, J = 21 Hz, 1 H), 5.10 (d, J = 21.7 Hz,
1 H), 5.16 (d, J = 4.7 Hz, 1 H), 6.96–7.18 (m, 8 H), 7.25–7.40 (m,
10 H), 7.40–7.53 (m, 2 H).
13C NMR (CDCl3, 62.9 MHz): d = 15.7–16.6 (m), 53.5 (d, JP–C
=
13C NMR (CDCl3, 62.9 MHz): d = 16.1–16.5 (m), 52.6 (d, JP–C
=
152.8 Hz), 55.4 (d, JP–C = 156.6 Hz), 57.9, 58.0, 62.3–63.6 (m),
85.0, 85.5, 127.6, 127.8, 128.0, 128.1, 128.2, 128.3–128.8 (m),
128.9, 129.4–129.9 (m), 131.3, 132.2, 133.6, 166.8 (b-lactam CO),
166.9 (b-lactam CO).
154.7 Hz), 54.6 (d, JP–C = 158.5 Hz), 55.1, 55.2, 58.0, 58.1, 62.4–
63.4 (m), 84.9, 85.4, 113.2, 113.3, 113.5, 113.9, 123.4, 124.0,
125.4, 125.6, 130.0, 130.3, 130.9–131.4 (m), 159.3–159.5 (m),
159.6, 159.7, 159.8, 166.8 (d, JP–C = 5.0 Hz), 167.0 (d, JP–C
=
31P NMR (CDCl3, 101.25 MHz, H3PO4): d = 18.70 (minor), 19.11
(major).
5.0 Hz).
31P NMR (CDCl3, 101.25 MHz, H3PO4): d = 18.87 (minor), 19.37
(major).
Anal. Calcd for C21H26NO5P: C, 62.51; H, 6.50; N, 3.47. Found: C,
62.32; H, 6.40; N, 3.40.
Anal. Calcd for C23H30NO7P: C, 59.59; H, 6.53; N, 3.02. Found: C,
59.53; H, 6.45; N, 2.96.
Diethyl [(3-Phenoxy-2-oxo-4-phenylazetidin-1-yl)phenylmeth-
yl]phosphonate (3f)
Colorless oil; mixture of two diastereoisomers.
1H NMR (CDCl3, 250 MHz): d = 1.0–1.20 (m, 9 H), 1.33 (t,
J = 7.0 Hz, 3 H), 3.75–4.10 (m, 6 H), 4.10–4.28 (m, 2 H), 4.90 (d,
Diethyl {(4-Methoxyphenyl)-[2-(4-methoxyphenyl)-3-phenoxy-
4-oxoazetidin-1-yl]methyl}phosphonate (3h)
Colorless oil; mixture of two diastereoisomers.
Synthesis 2010, No. 20, 3504–3508 © Thieme Stuttgart · New York

3508
B. Kaboudin, M. B. Afsharinezhad
PAPER
1H NMR (CDCl3, 250 MHz): d = 1.00–1.28 (m, 9 H), 1.35 (t,
J = 7 Hz, 3 H), 3.65 (s, 3 H), 3.66 (s, 3 H), 3.71 (s, 3 H), 3.78 (s,
3 H), 3.8–4.05 (m, 5 H), 4.05–4.25 (m, 3 H), 4.82 (d, J = 20.7 Hz,
1 H), 4.96 (d, J = 4.7 Hz, 1 H), 5.19 (d, J = 21.7 Hz, 1 H), 5.31 (d,
J = 4.5 Hz, 2 H), 5.40 (d, J = 4.7 Hz, 1 H), 6.45–6.62 (m, 6 H),
6.62–6.92 (m, 8 H), 6.93–7.15 (m, 8 H), 7.24 (d, J = 8.7 Hz, 2 H),
7.42 (d, J = 8.5 Hz, 2 H).
(4) Ishiguri, Y.; Yamada, Y.; Kato, T.; Sasaki, M.; Mukai, K.
Eur. Pat. Appl., EP 82-301905, 1982; Chem. Abstr. 1983, 98,
102686u.
(5) (a) Giannousis, P. P.; Bartlett, P. A. J. Med. Chem. 1987, 30,
1603. (b) Maier, L.; Lea, P. J. Phosphorus Sulfur Relat.
Elem. 1983, 17, 1. (c) Baylis, E. K.; Campbell, C. D.;
Dingwall, J. G. J. Chem. Soc., Perkin Trans. 1 1984, 2845.
(d) Hilderbrand, R. L. In The Role of Phosphonates in
Living Systems; CRC Press: Boca Raton, 1982.
(e) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon
Relat. Elem. 1991, 63, 193.
(6) Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B. Chem. Rev.
2004, 104, 5823.
(7) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med.
Chem. 1986, 29, 29.
13C NMR (CDCl3, 62.9 MHz): d = 16.1–16.6 (m), 53.0 (d, JP–C
154.3 Hz), 54.9 (d, JP–C = 158.5 Hz), 55.0–55.2 (m), 62.5 (d, JP–C
=
=
7.5 Hz), 62.9 (d, JP–C = 6.9 Hz), 62.6–63.7 (m), 81.4, 81.9, 113.1,
113.2, 113.5, 114.0, 115.5, 121.9, 123.3, 123.9, 124.8, 125.0, 129.1,
130.2, 130.5, 130.9–131.5 (m), 156.9, 159.4, 159.6–159.9 (m),
165.6 (d, JP–C = 5.0 Hz), 165.7 (d, JP–C = 5.0 Hz).
31P NMR (CDCl3, 101.25 MHz, H3PO4): d = 18.83 (major), 19.31
(minor).
(8) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M.
J. Med. Chem. 1989, 32, 1652.
(9) Hassal, C. H. In Antibiotics, Vol. 6; Hahn, F. E., Ed.;
Springer Verlag: Berlin, 1983, 1.
Anal. Calcd for C28H32NO7P: C, 62.25; H, 6.43; N, 2.79. Found: C,
62.32; H, 6.35; N, 2.70.
(10) (a) Poole, K. Cell. Mol. Life Sci. 2004, 61, 2200.
(b) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M.
Eur. J. Org. Chem. 1999, 3223. (c) Dürkheimer, W.;
Blumbach, J.; Lattrell, R.; Scheunemann, K. H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 180. (d) Chemistry and
Biology of b-Lactam Antibiotics, Vols. 1-3; Morin, R. B.;
Gorman, M., Eds.; Academic Press: New York, 1982.
(11) Southgate, R.; Branch, C.; Coulton, S.; Hunt, E. Recent
Progress in the Chemical Synthesis of Antibiotics and
Related Microbial Products, Vol. 2; Lukacs, G., Ed.;
Springer-Verlag: Berlin, 1993.
(12) (a) Miller, M. J. Acc. Chem. Res. 1986, 19, 49.
(b) Hegedus, L. S. Acc. Chem. Res. 1996, 28, 299.
(c) Barrett, M. A.; Sturgess, M. A. Tetrahedron 1988, 44,
5615.
(13) Staüdinger, H. Justus Liebigs Ann. Chem. 1907, 356, 51.
(14) (a) Kukhar, V. P.; Hudson, H. R. In Aminophosphonic and
Aminophosphinic Acids; John Wiley & Sons: Chichester,
2000. (b) Bhagat, S.; Chakraborti, A. K. J. Org. Chem. 2007,
72, 1263. (c) Kaboudin, B. Phosphorus, Sulfur Silicon Relat.
Elem. 2002, 177, 1749.
Diethyl {(4-Fluorophenyl)-[2-(4-fluorophenyl)-3-methoxy-4-
oxo-azetidin-1-yl]methyl}phosphonate (3i)
Colorless oil; mixture of two diastereoisomers.
1H NMR (CDCl3, 250 MHz): d = 0.98–1.25 (m, 9 H), 1.31 (t,
J = 7.0 Hz, 3 H), 3.02 (s, 6 H), 3.73–4.05 (m, 6 H), 4.07–4.23 (m,
2 H), 4.56 (d, J = 4.75 Hz, 1 H), 4.68 (dd, J = 4.5, 1.5 Hz, 1 H), 4.77
(d, J = 4.7 Hz, 1 H), 4.78 (d, J = 21.3 Hz, 1 H), 5.11 (d,
J = 21.5 Hz, 1 H), 5.17 (d, J = 5.0 Hz, 1 H), 6.63–6.88 (m, 4 H),
6.93–7.22 (m, 8 H), 7.23–7.36 (m, 2 H), 7.37–7.48 (m, 2 H).
13C NMR (CDCl3, 62.9 MHz): d = 16.0–16.5 (m), 52.3 (JP–C
=
155.3 Hz), 54.6 (JP–C = 157.8 Hz), 58.0, 58.1, 62.4–63.2 (m), 63.3–
63.7 (m), 85.0, 85.5, 114.5, 114.6–115.0 (m), 115.1, 115.3, 115.5,
115.8, 127.3, 128.1 (JC–F = 3.1 Hz), 129.4 (JC–F = 2.5 Hz), 130.4
(JC–F = 8.2 Hz), 130.7 (JC–F = 8.2 Hz), 131.4–131.9 (m), 160.4–
160.8 (m), 164.5–164.8 (m), 166.7 (d, JP–C = 5.0 Hz), 166.8 (d,
JP–C = 5.0 Hz).
31P NMR (CDCl3, 101.25 MHz, H3PO4): d = 18.33 (d, JP–F = 2.2 Hz;
major), 18.72 (d, JP–F = 2.6 Hz; minor).
Anal. Calcd for C21H24NO5F2P: C, 57.38; H, 5.51; N, 3.19. Found:
C, 57.52; H, 5.35; N, 3.20.
(15) Gancarz, R.; Wieczorek, J. S. Synthesis 1978, 625.
(16) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971,
36, 1379.
(17) Worms, K. H.; Schmidt-Dunker, M. In Organic Phosphorus
Compounds, Vol. 7; Kosolapoff, G. M.; Marier, L., Eds.;
John Wiley & Sons: New York, 1976, 1.
Acknowledgment
The authors gratefully acknowledge support by the Institute for Ad-
vanced Studies in Basic Sciences (IASBS) Research Council under
grant No. G2009IASBS120.
(18) Barycki, J.; Mastalerz, P.; Soroka, M. Tetrahedron Lett.
1970, 36, 3147.
(19) (a) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron Lett.
2002, 43, 4633. (b) Koster, W. H.; Zahler, R.; Chang, H. W.;
Cimarusti, C. M.; Jacobs, G. A.; Perri, M. J. Am. Chem. Soc.
1983, 105, 3743. (c) Shiozaki, M.; Masuko, H. Heterocycles
1984, 22, 1727. (d) Campbell, M. M.; Carruthers, N. I.;
Mickel, S. J. Tetrahedron 1982, 38, 2513. (e) Stevens, C.
V.; Vekemans, W.; Moonen, K.; Rammeloo, T. Tetrahedron
Lett. 2003, 44, 1619.
(20) (a) Kaboudin, B.; Moradi, K. Synthesis 2006, 2339.
(b) Kaboudin, B.; Jafari, E. Synthesis 2006, 3063.
(c) Kaboudin, B.; Moradi, K.; Sardarian, A. R. ARKIVOC
2007, (xiii), 210. (d) Kaboudin, B.; Jafari, E. Synthesis 2006,
1823.
References
(1) (a) Engel, R. Chem. Rev. 1977, 77, 349. (b) Hiratake, J.;
Oda, J. Biosci., Biotechnol., Biochem. 1997, 61, 211.
(c) Schug, K. A.; Lindner, W. Chem. Rev. 2005, 105, 67.
(d) Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev.
2004, 104, 6177. (e) Palacios, F.; Alonso, C.; de los Santos,
J. M. Curr. Org. Chem. 2004, 8, 1481.
(2) Dingwall, J. G.; Campell, C. D.; Baylis, E. K. UK Pat. Appl.,
1 542 938, 1979; Chem. Abstr. 1979, 88, 105559j.
(3) Kafarski, P.; Lejczak, B.; Tyka, R.; Koba, L.; Pliszczak, E.;
Wieczorek, P. J. Plant Growth Regul. 1995, 14, 199.
(21) Kaboudin, B.; Moradi, K. Tetrahedron Lett. 2005, 46, 2689.
Synthesis 2010, No. 20, 3504–3508 © Thieme Stuttgart · New York