Synthesis of phosphonobenzocarbacephems by intramolecular radical cyclization of haloaryl-substituted β-lactams

Article abstract of DOI:10.1002/ejoc.200901351

A series of benzo-fused tricyclic β-lactams, most of them phosphonobenzocarbacephems, were prepared in a straightforward way starting from phosphonoazadienes. In this paper, the synthetic route including a Staudinger reaction towards the β-lactams, followed by radical ring closing with tributyltin hydride and AIBN, which resulted in the envisaged tricyclic compounds, is reported.

Full text of DOI:10.1002/ejoc.200901351

FULL PAPER
DOI: 10.1002/ejoc.200901351
Synthesis of Phosphonobenzocarbacephems by Intramolecular Radical
Cyclization of Haloaryl-Substituted β-Lactams
Sarah Van der Jeught,[a] Kurt G. R. Masschelein,[a] and Christian V. Stevens*[a]
Keywords: Lactams / β-Lactamases / Radical reactions / Cyclization / Benzocarbacephems / Phosphonates
A series of benzo-fused tricyclic β-lactams, most of them
phosphonobenzocarbacephems, were prepared in a straight-
forward way starting from phosphonoazadienes. In this pa-
per, the synthetic route including a Staudinger reaction
towards the β-lactams, followed by radical ring closing with
tributyltin hydride and AIBN, which resulted in the envis-
aged tricyclic compounds, is reported.
phono-α-aminobisphosphonates[6a] and bisphosphonoaza-
dienes.[6b] These good results prompted us to focus also on
the preparation of β-lactams bearing a phosphonate sub-
stituent, using these as precursors for benzo-fused tricyclic
β-lactams. Thus combining the biological activity of the
phosphonate moiety and the benzocarbacephem structure.
We investigated the (racemic) synthesis of phosphono-sub-
stituted tricyclic β-lactams, particularly benzocarba-
cephems, by intramolecular radical cyclization of the
haloaryl-substituted β-lactams.
Introduction
The synthesis of novel 2-azetidinone-based heterocycles
is still intensively investigated since the discovery of penicil-
lin in 1929. In the early years, the research was mainly fo-
cused on the improvement of the antibacterial properties of
these compounds. The discovery of potent elastase-in-
hibiting properties for structurally modified cephalosporin
antibiotics in 1986 led to the investigation of other than
antibacterial properties of these β-lactams. Soon various
other activities were discovered such as thrombine inhibi-
tion, human cytomegalovirus protease inhibition, cathepsin
inhibition and many others.[1] The antibacterial properties
nevertheless remained important research topics. Due to the
popularity of β-lactams as drugs against bacterial infec-
tions, numerous bacteria have developed resistance to these
traditional drug therapies by the presence of β-lactamases.
These enzymes break the β-lactam ring and inactivate the
drug. Several strategies were evaluated to contravene this
action, the alteration of the structure of the β-lactam-anti-
biotic to render it insensitive to the destroying effect being
one of them. Another possible solution lies in the combina-
tion of the β-lactam and a compound inactivating the β-
lactamase. These β-lactamase inhibitors can be completely
distinct structures like clavulanic acid, or β-lactam deriva-
tives working synergetically with the antibiotic. Known β-
lactamase inactivators are, among others, benzocarba-
penems and benzocarbacephems, the latter class being the
most investigated one.[2–4]
Results and Discussion
The starting compounds for the synthesis of the β-lactam
precursors are dialkyl (1E)-3-oxoprop-1-enylphosphonates
1. These compounds can be prepared in a few steps, starting
from epibromohydrin.[6a,7] Imination of the phosphono-
aldehydes 1 with 2-bromobenzylamine in the presence of
MgSO4 resulted in 4-phosphono-1-aza-1,3-dienes 2a and 2d
in good yields. A few other amines (without haloaryl moi-
ety, so not suited to enable radical ring-closing in the final
step) were also evaluated to prove the general character of
the route towards the monocyclic β-lactams (Scheme 1,
Table 1).
Several reactivity studies and research on the synthetic
use of phosphonoazadienes[5,6] have been conducted over
the past years. These precursors have already proven their
usefulness in the preparation of potentially active phos-
phonoaziridines,[5a,5b] phosphonylated γ-lactams,[5c] γ-phos-
Scheme 1.
The E-imines 2 resulted in the corresponding phos-
phono-β-lactams 3 by the Staudinger reaction with the suit-
able acid chlorides and in the presence of Et3N (Scheme 2,
Table 2). In the case of the propargylimine 2e however, a
slight change in the reaction circumstances was needed. If
[a] Department of Organic Chemistry, Faculty of Bioscience Engi-
neering, Ghent University,
Coupure Links 653, 9000 Ghent, Belgium
E-mail: Chris.stevens@UGent.be
Eur. J. Org. Chem. 2010, 1333–1338
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Van der Jeught, K. G. R. Masschelein, C. V. Stevens
FULL PAPER
Table 1. Synthesis of 4-phosphono-1-aza-1,3-dienes.
Entry R1
R2
Product
Yield (%)
1
2
3
4
5
Me
Me
Me
Et
2-Br-Bn
iPr
p-MeO-Ph
2-Br-Bn
propargyl
2a
2b
2c
2d
2e
97
83
99
97
97
Scheme 3.
Table 3. Intramolecular aryl radical cyclization.
Et
Entry R1
R2
R3
Product
Yield (%)
the aldimine 2e was dissolved in CH2Cl2 together with Et3N
before adding the acid chloride, an isomerization of the
double bond occurred, leading to several end products.
Therefore, the acid chloride was first stirred in the presence
of Et3N for 20 min to form the ketene, then followed by
addition of the imine. In this way, isomerization could be
avoided and only β-lactam 3h was formed. The racemic β-
lactams 3 were all obtained as single cis-diastereoisomers.
Purification by column chromatography sometimes resulted
in a drop of the yield, due to the large affinity of the com-
pounds for the silica gel.
1
2
3
4
5
Me
Me
Et
Et
Me
2-Br-Bn Ph
2-Br-Bn Bn
2-Br-Bn Ph
2-Br-Bn Bn
4a
4b
4c
4d
4e
62[a]
66[a]
69[a]
71[a]
iPr
2-Br-Ph
82[b] (80:20)
(anti/syn)
[a] After purification by column chromatography. [b] Yield of crude
product (mixture of isomers).
The radical cyclization of 3d to 4e was a special case in
this series. The oxygen in the side chain is bearing the
haloaryl moiety instead of the nitrogen atom of the β-lac-
tam-ring. Treatment of this haloarene under similar condi-
tions for the preparation of benzocarbacephems 4a–d gave
the fused tricyclic β-lactam 4e (Scheme 4). This compound
was formed as a mixture of diastereomers, namely epimers
at the newly formed C5 stereocentre. The relative stereo-
chemistry of this new chiral centre could be determined by
the coupling constants of protons H5 and H6 and the ratio
Scheme 2.
was defined by a combination of 31P NMR and H NMR
1
Table 2. Synthesis of phosphono β-lactams.
spectra of the crude reaction mixture (before purification).
These findings are in accordance with similar results ob-
tained by Alcaide et al.[2] on derivatives without a phos-
phonate substituent. The syn isomer could not be isolated.
Entry R1
R2
R3
Product
Yield (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Et
2-Br-Bn
2-Br-Bn
iPr
Ph
Bn
Ph
2-Br-Ph
Ph
Ph
Bn
Ph
3a
3b
3c
3d
3e
3f
88[a]
70[a]
74[a]
60[a]
76[a]
62[a]
56[a]
66[a]
iPr
p-MeO-Ph
2-Br-Bn
2-Br-Bn
propargyl
Et
Et
3g
3h
[a] After purification by column chromatography.
Scheme 4.
Having obtained the monocyclic precursors bearing a
haloaryl moiety (3a,b,d,f,g), the next step was the conver-
sion into benzo-fused tricyclic β-lactams 4. This key ring-
closing step was performed through intramolecular aryl-
radical cyclization. The β-lactams 3 were treated with tribu-
tyltin hydride and AIBN in dry toluene at reflux tempera-
ture. After 3–10 h the reaction was completed and the
benzocarbacephems 4 were present in the reaction mixture
as single diastereomers (Scheme 3, Table 3). To remove the
organotin halides, several types of work-up and purification
procedures were evaluated. It turned out to be extremely
difficult to remove all the traces of this reagent, as is already
well known in literature.[8] The best results were obtained
by washing the reaction with a solution of KF in water.[9]
In all of the cases, however, column chromatography was
required and resulted, without exception, in a considerable
drop of the yield.
Conclusions
The racemic synthesis of phosphono-substituted benzo-
carbacephems was accomplished by starting from the corre-
sponding β-lactams. The key reaction consisted of an intra-
molecular radical cyclization using Bu3SnH and AIBN and
also proved to be suitable for other fused tricyclic β-lactams
bearing a phosphonate moiety. The possible anti-β-lactam-
ase activity of these compounds is currently under investi-
gation.
Experimental Section
Synthesis of 4-Phosphono-1-aza-1,3-dienes 2a–e: All phosphonyl-
ated α,β-unsaturated aldimines 2a–e were prepared by mixing di(m)
1334
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1333–1338

Phosphonobenzocarbacephems by Intramolecular Radical Cyclization
ethyl (1E)-3-oxoprop-1-enylphosphonate (1) with 1 equiv. of amine
and 0.5 equiv. of MgSO4 in dry dichloromethane. After stirring for
2–4 h at room temperature with a CaCl2 tube, the MgSO4 was fil-
tered off and the dichloromethane was evaporated in vacuo. The
imines 2a–e were isolated as yellowish oils in high purity and yield.
HC=CHP), 145.31 (2JCP = 5.8 Hz, HC=CHP), 161.94 (3JCP
30.0 Hz, HC=N) ppm. 31P NMR (121 MHz, CDCl3): δ = 16.45
ppm. IR: ν
= 1018, 1047 (P–O), 1245 (P=O) cm–1. MS (ESI,
=
˜
max.
pos. mode): m/z (%) = 230 (100/100) [M + H+].
Synthesis of Dialkyl {(E)-2-[(cis)-4-Oxoazetidin-2-yl]vinyl}-
phosphonates 3a–h: As a representative example, the synthesis of
dimethyl {(E)-2-[(cis)-1-(2-bromobenzyl)-4-oxo-3-phenoxyazetidin-
2-yl]vinyl}phosphonate (3a) is described here. A solution of di-
Dimethyl [(1E,3E)-3-(2-Bromobenzylimino)prop-1-en-1-yl]phosphon-
ate (2a): Yellowish oil (0.95 g, 97%). 1H NMR (300 MHz, CDCl3):
3
δ = 3.78 [d, JHP = 11.0 Hz, 6 H, P(O)(OCH3)2], 4.83 (s, 2 H,
2
methyl
[(1E,3E)-3-(2-bromobenzylimino)prop-1-en-1-yl]phos-
phonate (2a, 0.95 g, 2.86 mmol) and Et3N (0.87 g, 8.58 mmol) was
stirred in dry CH2Cl2 (15 mL) under nitrogen at 0 °C. To this solu-
tion, phenoxyacetyl chloride was added dropwise (0.63 g,
3.72 mmol) and then stirred for 20 h at room temperature. Sub-
sequently, the reaction mixture was poured into water (20 mL) and
extracted with CH2Cl2 (2ϫ15 mL). The combined organic layers
were dried (MgSO4), filtered and the solvent was removed in vacuo
to yield dimethyl {(E)-2-[(cis)-1-(2-bromobenzyl)-4-oxo-3-phen-
oxyazetidin-2-yl]vinyl}phosphonate (3a). The product was purified
through column chromatography on silica gel (petroleum ether/
EtOAc, 3:7) and was isolated in 88% yield (1.17 g).
NCH2), 6.23 (dd, JHP = 17.9, J = 17.3 Hz, 1 H, HC=CHP), 7.17
(ddd, J = 17.3, 3JHP = 12.1, J = 8.5 Hz, 1 H, HC=CHP), 7.13–7.59
(m, 4 H, 4ϫ CHarom.), 8.08 (dd, J = 8.5, J = 1.4 Hz, 1 H, HC=N)
ppm. 13C NMR (75 MHz, CDCl3): δ = 52.79 (2JCP = 5.8 Hz, CH3),
52.80 (2JCP = 5.8 Hz, CH3), 64.52 (CH2), 123.81 (Cquat.,arom.),
126.66 (1JCP = 189.2 Hz, HC=CHP), 127.72 (CHarom.), 128.94
(CHarom.), 130.07 (CHarom.), 132.77 (CHarom.), 137.40 (Cquat.,arom.),
146.46 (2JCP = 5.8 Hz, HC=CHP), 162.33 (3JCP = 30.0 Hz, HC=N)
ppm. 31P NMR (121 MHz, CDCl ): δ = 19.35 ppm. IR: ν
=
˜
3
max.
1028 (br., P–O), 1251 (P=O) cm–1. MS (ESI, pos. mode): m/z (%)
= 332/334 (100/100) [M + H+].
Dimethyl
[(1E,3E)-3-(Isopropylimino)prop-1-en-1-yl]phosphonate
Dimethyl {(E)-2-[(cis)-1-(2-Bromobenzyl)-4-oxo-3-phenoxyazetidin-
2-yl]vinyl}phosphonate (3a): Yellow oil (1.17 g, 88%). 1H NMR
(2b): Yellowish oil (1.33 g, 83%) Already known.
Dimethyl [(1E,3E)-3-[(4-Methoxyphenyl)imino]prop-1-en-1-yl]phos-
phonate (2c): Yellowish oil (1.21 g, 99%). 1H NMR (300 MHz,
3
(CDCl3, 300 MHz): δ = 3.48 [d, JHP = 11.0 Hz, 3 H, P(O)OCH3],
3
3.52 [d, JHP = 11.0 Hz, 3 H, P(O)OCH3], 4.35 (d, J = 14.9 Hz, 1
3
CDCl3): δ = 3.80 [d, JHP = 11.0 Hz, 6 H, 2ϫ P(O)OCH3], 3.84 (s,
4
H, NCHAHBPh), 4.40 (dddd, J = 7.7, J = 4.7, JHP = 1.4, J =
2
3 H, Cquat.,arom.OCH3), 6.31 (dd, JHP = 17.9, J = 17.3 Hz, 1 H,
0.8 Hz, 1 H, NCH), 4.82 (d, J = 14.9 Hz, 1 H, NCHAHBPh), 5.35
HC=CHP), 6.93 (d, J = 9.1 Hz, 2 H, 2ϫ CHarom.), 7.23 (d, J =
2
(d, J = 4.7 Hz, 1 H, CHOPh), 5.86 (ddd, JHP = 19.3, J = 17.3, J
3
9.1 Hz, 2 H, 2ϫ CHarom.), 7.28 (ddd, JHP = 20.4, J = 17.3, J =
= 0.8 Hz, 1 H, CHP), 6.61 (ddd, 3JHP = 21.2, J = 17.3, J = 7.7 Hz,
1 H, HC=CHP), 6.88–7.01 (m, 3 H, 3ϫ CHarom.), 7.18–7.38 (m, 5
H, 5ϫ CHarom.), 7.57–7.60 (m, 1 H, CHarom.) ppm. 13C NMR
(75 MHz, CDCl3): δ = 45.27 (NCH2Ph), 52.27 [2JCP = 5.8 Hz,
8.8 Hz, 1 H, HC=CHP), 8.22 (dd, J = 8.8, J = 1.7 Hz, 1 H, HC=N)
ppm. 13C NMR (75 MHz, CDCl3): δ = 52.80 [2JCP = 5.8 Hz, 2ϫ
P(O)OCH3], 55.51 (Cquat.,arom.OCH3), 114.51 (2ϫ CHarom.), 122.74
(2ϫ CHarom.)
(Cquat.,arom.), 146.99 (2JCP = 5.8 Hz, HC=CHP), 156.44 (3JCP
30.0 Hz, HC=N), 159.52 (Cquat.,arom.OCH3) ppm. 31P NMR
, = 190.4 Hz, HC=CHP), 143.15
126.31 (1JCP
P(O)OCH3], 52.38 [2JCP = 5.8 Hz, P(O)OCH3], 60.11 (3JCP
=
=
25.4 Hz, NCH), 81.82 (CHOPh), 115.23 (2ϫ CHarom.), 122.50
(CHarom.), 122.82 (1JCP = 185.8 Hz, CHP), 123.99 (Cquat.,arom.),
128.13 (CHarom.), 129.64 (2ϫ CHarom.), 130.15 (CHarom.), 131.41
(121 MHz, CDCl ): δ = 19.58 ppm. IR: ν
= 1031 (P–O), 1053
˜
3
max.
(P–O), 1250 (P=O), 1506, 1597 cm–1. MS (ESI, pos. mode): m/z
(CHarom.), 133.24 (CHarom.), 133.86 (Cquat.,arom.), 145.13 (2JCP
=
(%) = 270 (100) [M + H+].
5.8 Hz, HC=CHP), 156.76 (Cquat.,arom.), 164.61 (C=O) ppm. 31P
Diethyl [(1E,3E)-3-(2-Bromobenzylimino)prop-1-en-1-yl]phosphon-
ate (2d): Pale yellow oil (0.91 g, 97%). 1H NMR (300 MHz,
CDCl3): δ = 1.35 [t, J = 7.2 Hz, 6 H, P(O)(OCH2CH3)2], 4.14 [dq,
2JHP = 7.7, J = 7.2 Hz, 4 H, P(O)(OCH2CH3)2], 4.82 (s, 2 H,
NCH2), 6.26 (dd, 2JHP = 17.6, J = 17.6 Hz, 1 H, HC=CHP), 7.08–
NMR (121 MHz, CDCl ): δ = 18.55 ppm. IR: ν
= 1026 (P–O),
˜
3
max.
1232 (P=O), 1761 (C=O) cm–1. MS (ESI, pos. mode): m/z (%) =
466/468 (100) [M + H+]. Chromatography: PE/EtOAc (3:7) Rf =
0.20.
Dimethyl
{(E)-2-[(cis)-3-Benzyloxy-1-(2-bromobenzyl)-4-oxoazet-
7.24 (m,
2 H, HC=CHP, CHarom.),7.28–7.36 (m, 2 H, 2ϫ
idin-2-yl]vinyl}phosphonate (3b): Yellowish oil (1.01 g, 70%). 1H
CHarom.), 7.56–7.60 (m, 1 H, CHarom.), 8.08 (dd, J = 8.8, J = 1.7 Hz,
1 H, HC=N) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.49 (3JCP
= 5.8 Hz, 2ϫ OCH2CH3), 62.42 (2JCP = 5.8 Hz, 2ϫ OCH2CH3),
64.63 (NCH2), 123.91 (Cquat.,arom.), 127.82 (CHarom.), 128.34 (1JCP
= 189.2 Hz, HC=CHP), 129.03 (CHarom.), 130.17 (CHarom.), 132.86
(CHarom.), 137.55 (Cquat.,arom.), 145.72 (2JCP = 5.8 Hz, HC=CHP),
162.69 (3JCP = 30.0 Hz, HC=N) ppm. 31P NMR (121 MHz,
3
NMR (CDCl3, 300 MHz): δ = 3.62 [d, JHP = 11.0 Hz, 3 H,
P(O)OCH3], 3.65 [d, JHP = 11.0 Hz, 3 H, P(O)OCH3], 4.13–4.18
3
(m, 1 H, NCH), 4.29 (d, J = 14.8 Hz, 1 H, NCHAHBPh), 4.59
(d, J = 11.6 Hz, 1 H, OCHAHBPh), 4.68 (d, J = 11.6 Hz, 1 H,
OCHAHBPh), 4.74 (d, J = 14.8 Hz, 1 H, NCHAHBPh), 4.80 (d,
2
CHOPh, = 5.0 Hz, 1 H,J), 5.85 (dd, JHP = 19.5, J = 17.1 Hz, 1
3
H, CHP), 6.62 (ddd, JHP = 21.5, J = 17.1, J = 7.4 Hz, 1 H,
CDCl ): δ = 16.50 ppm. IR: νmax. = 1020 (P–O), 1242 (P=O) cm–1.
˜
3
HC=CHP), 7.14–7.22 (m, 1 H, CHarom.), 7.28–7.38 (m, 7 H, 7ϫ
MS (ESI, pos. mode): m/z (%) = 360/362 (100/100) [M + H+].
CHarom.), 7.55 (ps d, J = 8.3 Hz, 1 H, CHarom.) ppm. 13C NMR
Chromatography: PE/EtOAc (2:8) Rf = 0.41.
(75 MHz, CDCl3, ref TMS): δ = 44.92 (NCH2Ph), 52.45 [2JCP
=
[Diethyl (1E,3E)-3-(Prop-2-ynylimino)prop-1-en-1-yl]phosphonate
(2e): Yellowish oil (2.33 g, 97%). H NMR (300 MHz, CDCl3): δ
4.6 Hz, P(O)OCH3], 52.52 [2JCP = 4.6 Hz, P(O)OCH3], 59.95 (3JCP
= 24.2 Hz, NCH), 73.03 (OCH2Ph), 83.59 (CHOPh), 121.76 (1JCP
= 187.0 Hz, CHP), 123.88 (Cquat.,arom.), 128.03 (CHarom.), 128.17
(2ϫ CHarom.), 128.22 (CHarom.), 128.48 (2ϫ CHarom.), 129.95
1
= 1.36 (t, J = 7.2 Hz, 6 H, 2ϫ OCH2CH3), 2.58 (t, J = 2.2 Hz, 1
2
H, NCH2CCH), 4.14 (dq, JHP = 7.7, J = 7.2 Hz, 4 H, 2ϫ
2
OCH2CH3), 4.51 (s, 2 H, NCH2), 6.31 (dd, JHP = 17.6, J = (CHarom.), 131.21 (CHarom.), 133.14 (CHarom.), 134.08 (Cquat.,arom.),
3
17.4 Hz, 1 H, HC=CHP), 7.14 (ddd, JHP = 20.4, J = 17.4, J =
8.8 Hz, 1 H, HC=CHP), 8.30 (dd, J = 8.8, J = 1.7 Hz, 1 H, HC=N)
ppm. 13C NMR (75 MHz, CDCl3): δ = 16.35 (3JCP = 5.8 Hz, 2ϫ
136.30 (Cquat.,arom.), 146.17 (2JCP = 5.8 Hz, HC=CHP), 166.41
(C=O) ppm. 31P NMR (121 MHz, CDCl3): δ = 19.02 ppm. IR:
ν
= 1025 (P–O), 1249 (P=O), 1757 (C=O) cm–1. MS (ESI, pos.
˜
max.
OCH2CH3), 47.16 (NCH2), 62.25 (2JCP = 5.8 Hz, 2ϫ OCH2CH3), mode): m/z (%) = 480/482 (100) [M + H+]. Chromatography: PE/
76.46 (NCH2CCH), 77.79 (NCH2CCH), 128.37 (1JCP = 189.2 Hz,
EtOAc (4:6) Rf = 0.11.
Eur. J. Org. Chem. 2010, 1333–1338
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1335

S. Van der Jeught, K. G. R. Masschelein, C. V. Stevens
FULL PAPER
Dimethyl
vinyl}phosphonate (3c): Pale yellow crystals (1.63 g, 74%). 1H NMR 1.21 [t, J = 7.2 Hz, 3 H, P(O)OCH2CH3], 3.67–3.94 [m, 4 H, 2ϫ
(CDCl3, 300 MHz): δ = 1.25 [d, J = 6.6 Hz, 3 H, CH(CH3)], 1.30 P(O)OCH2CH3], 4.33 (d, J = 14.9 Hz, 1 H, NCHAHBPh), 4.40
{(E)-2-[(cis)-1-Isopropyl-4-oxo-3-phenoxyazetidin-2-yl]- (CDCl3, 300 MHz): δ = 1.20 [t, J = 7.2 Hz, 3 H, P(O)OCH2CH3],
3
4
[d, J = 6.6 Hz, 3 H, CH(CH3)], 3.49 [d, JHP = 11.0 Hz, 3 H, (dddd, J = 7.7, J = 4.4, J = 1.0, JHP = 1.1 Hz, 1 H, NCH), 4.83
3
P(O)OCH3], 3.53 [d, JHP = 11.0 Hz, 3 H, P(O)OCH3], 3.92 [sept,
(d, J = 14.9 Hz, 1 H, NCHAHBPh), 5.35 (d, J = 4.4 Hz, 1 H,
J = 6.6 Hz, 1 H, CH(CH3)2], 4.54 (dd, J = 8.3, J = 4.4 Hz, 1 H,
CHOPh), 5.90 (ddd, 2JHP = 18.2, J = 17.1, J = 1.0 Hz, 1 H, CHP),
NCH), 5.29 (d, J = 4.4 Hz, 1 H, CHOPh), 5.99 (dd, JHP = 17.9, 6.59 (ddd, 3JHP = 20.9, J = 17.1, J = 7.7 Hz, 1 H, HC=CHP), 6.88–
2
3
J = 17.3 Hz, 1 H, HC=CHP), 6.75 (ddd, JHP = 21.2, J = 17.3, J 6.91 (m, 2 H, 2ϫ CHarom.), 6.99 (dd,
J = 7.5 Hz, 1 H,
= 8.3 Hz, 1 H, HC=CHP), 6.90–7.03 (m, 3 H, 3ϫ CHarom.), 7.21– CHarom.),7.18–7.37 (m, 5 H, 5ϫ CHarom.), 7.59 (ps d, J = 7.2 Hz,
7.33 (m, 2 H, 2ϫ CHarom.) ppm. 13C NMR (75 MHz, CDCl3): δ = 1 H, CHarom.) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.33 (3JCP
20.20 [CH(CH3)], 21.66 [CH(CH3)], 45.13 [NCH(CH3)2], 52.32 = 6.9 Hz, 2ϫ OCH2CH3), 45.28 (NCH2Ph), 60.21 (3JCP = 24.2 Hz,
[2JCP = 5.8 Hz, P(O)OCH3], 52.39 [2JCP = 5.8 Hz, P(O)OCH3],
59.11 (3JCP = 26.5 Hz, NCH), 80.68 (CHOPh), 115.20 (2ϫ
NCH), 61.93 (2JCP = 5.8 Hz, OCH2CH3), 62.02 (2JCP = 5.8 Hz,
OCH2CH3), 81.76 (CHOPh), 115.18 (2ϫ CHarom.), 122.48
CHarom.), 122.39 (CHarom.), 122.39 (1JCP = 185.8 Hz, HC=CHP), (CHarom.), 123.97 (Cquat.,arom.), 124.28 (1JCP = 184.6 Hz, CHP),
129.70 (2ϫ CHarom.), 147.28 (2JCP = 5.8 Hz, HC=CHP), 156.80
(Cquat.,arom.), 164.09 (C=O) ppm. 31P NMR (121 MHz, CDCl3): δ (CHarom.), 133.27 (CHarom.), 133.87 (Cquat.,arom.), 144.20 (2JCP
128.16 (CHarom.), 129.67 (2ϫ CHarom.), 130.18 (CHarom.), 131.41
=
= 18.50 ppm. IR: ν
= 1015, 1048 (P–O), 1245 (P=O), 1737
5.8 Hz, HC=CHP), 156.78 (Cquat.,arom.), 164.69 (C=O) ppm. 31P
˜
max.
(C=O) cm–1. MS (ESI, pos. mode): m/z (%) = 340 (100) [M + H+].
NMR (121 MHz, CDCl ): δ = 15.73 ppm. IR: ν
= 1022 (P–O),
˜
3
max.
M.p. 105–107 °C.
1233 (P=O), 1764 (C=O) cm–1. MS (ESI, pos. mode): m/z (%) =
494/496 (100) [M + H+]. Chromatography: PE/EtOAc (3:7) Rf =
0.24.
Dimethyl {(E)-2-[(cis)-3-(2-Bromophenoxy)-1-isopropyl-4-oxoazet-
idin-2-yl]vinyl}phosphonate (3d): Yellow oil (0.97 g, 60%). 1H NMR
(CDCl3, 300 MHz): δ = 1.25 [d, J = 6.6 Hz, 3 H, CH(CH3)], 1.30
Diethyl {(E)-2-[(cis)-3-Benzyloxy-1-(2-bromobenzyl)-4-oxoazetidin-
2-yl]vinyl}phosphonate (3g): Yellow oil (0.19 g, 56%). 1H NMR
(CDCl3, 300 MHz): δ = 1.24 [t, J = 7.2 Hz, 3 H, P(O)OCH2CH3],
1.28 [t, J = 7.2 Hz, 3 H, P(O)OCH2CH3], 4.13–4.17 (m, 1 H,
NCH), 4.28 (d, J = 15.1 Hz, 1 H, NCHAHBPh), 4.58 (d, J =
11.6 Hz, 1 H, OCHAHBPh), 4.67 (d, J = 11.6 Hz, 1 H, OCHA-
HBPh), 4.75 (d, J = 15.1 Hz, 1 H, NCHAHBPh), 4.80 (d, J =
5.0 Hz, 1 H, CHOPh), 5.89 (ddd, 2JHP = 18.9, J = 17.1, J = 1.1 Hz,
3
[d, J = 6.6 Hz, 3 H, CH(CH3)], 3.65 [d, JHP = 11.0 Hz, 3 H,
3
P(O)OCH3], 3.66 [d, JHP = 11.0 Hz, 3 H, P(O)OCH3], 3.91 [sept,
J = 6.6 Hz, 1 H, CH(CH3)2], 4.56 (dd, J = 8.3, J = 4.7 Hz, 1 H,
2
NCH), 5.28 (d, J = 5.0 Hz, 1 H, CHOPh), 6.06 (ddd, JHP = 18.2,
J = 17.3, J = 0.8 Hz, 1 H, CHP), 6.85 (ddd, 3JHP = 21.2, J = 17.3,
J = 8.3 Hz, 1 H, HC=CHP), 6.89 (dxt, J = 7.4, J = 1.7 Hz, 1 H,
CHarom.), 7.15 (dd, J = 8.3, J = 1.7 Hz, 1 H, CHarom.), 7.25 (ddd,
J = 8.3, J = 7.4, J = 1.7 Hz, 1 H, CHarom.), 7.50 (dd, J = 7.4, J =
1.7 Hz, 1 H, CHarom.) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.29
3
1 H, CHP), 6.62 (ddd, JHP = 21.5, J = 17.1, J = 7.4 Hz, 1 H,
HC=CHP), 7.14–7.22 (m, 1 H, CHarom.), 7.28–7.36 (m, 7 H, 7ϫ
CHarom.), 7.55 (ps d, J = 7.7 Hz, 1 H, CHarom.) ppm. 13C NMR
(75 MHz, CDCl3): δ = 16.37 (3JCP = 5.8 Hz, OCH2CH3), 16.45
[CH(CH3)], 21.74 [CH(CH3)], 45.26 [NCH(CH3)2], 52.72 [2JCP
=
5.8 Hz, P(O)OCH3], 52.80 [2JCP = 5.8 Hz, P(O)OCH3], 58.68 (3JCP
= 26.5 Hz, NCH), 81.68 (CHOPh), 112.23 (Cquat.,arom.), 115.59
(CHarom.), 122.63 (1JCP = 186.9 Hz, CHP), 123.79 (CHarom.),
(3JCP = 5.8 Hz, OCH2CH3), 44.99 (NCH2Ph), 60.07 (3JCP
24.2 Hz, NCH), 62.10 (2JCP = 5.8 Hz, OCH2CH3), 62.17 (2JCP
=
=
128.70 (CHarom.), 133.59 (CHarom.), 147.02 (2JCP
=
5.8 Hz,
5.8 Hz, OCH2CH3), 73.05 (OCH2Ph), 83.69 (CHOPh), 123.32
(1JCP = 187.0 Hz, CHP), 123.93 (Cquat.,arom.), 128.09 (CHarom.),
128.23 (2ϫ CHarom.), 128.26 (CHarom.), 128.54 (2ϫ CHarom.),
130.02 (CHarom.), 131.24 (CHarom.), 133.22 (CHarom.), 134.17
HC=CHP), 153.71 (Cquat.,arom.), 164.10 (C=O) ppm. 31P NMR
(121 MHz, CDCl ): δ = 18.48 ppm. IR: ν
= 1031, 1049 (P–O),
˜
3
max.
1245 (P=O), 1759 (C=O) cm–1. MS (ESI, pos. mode): m/z (%) =
418/420 (75) [M + H+]. Chromatography: Hex/EtOAc (1:1) Rf =
0.05.
(Cquat.,arom.), 136.42 (Cquat.,arom.), 145.26 (2JCP
=
5.8 Hz,
HC=CHP), 166.55 (C=O) ppm. 31P NMR (121 MHz, CDCl3): δ =
Dimethyl {(E)-2-[(cis)-1-(4-Methoxyphenyl)-4-oxo-3-phenoxyazet-
idin-2-yl]vinyl}phosphonate (3e): Pale brown oil (1.37 g, 76%). 1H
16.27 ppm. IR: νmax. = 1022, 1048 (P–O), 1248 (P=O), 1759 (C=O)
˜
cm–1. MS (ESI, pos. mode): m/z (%) = 508/510 (100) [M + H+].
Chromatography: PE/EtOAc (3:7) Rf = 0.16.
3
NMR (CDCl3, 300 MHz): δ = 3.52 [d, JHP = 11.0 Hz, 3 H,
3
P(O)OCH3], 3.55 [d, JHP = 11.0 Hz, 3 H, P(O)OCH3], 3.80 (s, 3
Diethyl {(E)-2-[(cis)-4-Oxo-3-phenoxy-1-(prop-2-ynyl)azetidin-2-yl]-
vinyl}phosphonate (3h): This preparation was slightly different from
the general method. In this case, the phenoxyacetyl chloride (0.48 g,
2.84 mmol) was first stirred together with Et3N (0.29 g, 2.84 mmol)
in dry CH2Cl2 (15 mL) under nitrogen atmosphere at 0 °C to form
the ketene. To this mixture, a solution of diethyl (1E,3E)-3-(prop-
2-ynylimino)prop-1-en-1-ylphosphonate (2e) in dry CH2Cl2 (5 mL)
was added dropwise and then stirred overnight at room tempera-
ture. The work-up was the same as in the general method and
yielded after purification 0.52 g (66%) of 3h.
4
H, OCH3), 4.98 (dddd, J = 6.3, J = 5.0, JHP = 1.9, J = 0.8 Hz, 1
2
H, NCH), 5.49 (d, J = 5.0 Hz, 1 H, CHOPh), 6.03 (ddd, JHP
=
17.9, J = 17.3, J = 0.8 Hz, 1 H, CHP), 6.80 (ddd, 3JHP = 22.9, J =
17.3, J = 6.3 Hz, 1 H, HC=CHP), 6.88 (d, J = 9.1 Hz, 2 H, 2ϫ
CHarom.), 6.97–7.06 (m, 3 H, 3ϫ CHarom.), 7.28–7.31 (m, 2 H, 2ϫ
CHarom.), 7.35 (d, J = 9.1 Hz, 2 H, 2ϫ CHarom.) ppm. 13C NMR
(75 MHz, CDCl3): δ = 52.36 [2JCP = 5.8 Hz, P(O)OCH3], 52.45
[2JCP = 5.8 Hz, P(O)OCH3], 55.53 (OCH3), 59.76 (3JCP = 25.4 Hz,
NCH), 81.01 (CHOPh), 114.62 (2ϫ CHarom.), 115.32 (2ϫ
CHarom.), 118.57 (2ϫ CHarom.), 122.69 (CHarom.), 122.75 (1JCP
=
185.8 Hz, CHP), 129.76 (2ϫ CHarom.), 130.22 (Cquat.,arom.), 144.80
Diethyl {(E)-2-[(cis)-4-Oxo-3-phenoxy-1-(prop-2-ynyl)azetidin-2-yl]-
vinyl}phosphonate (3h): Yellow oil (0.52 g, 66%). 1H NMR (CDCl3,
300 MHz): δ = 1.22 [t, J = 7.2 Hz, 3 H, P(O)OCH2CH3], 1.24 [t, J
= 7.2 Hz, 3 H, P(O)OCH2CH3], 2.32 (t, J = 2.2 Hz, 1 H,
NCH2CCH), 3.74–3.99 [m, 4 H, 2ϫ P(O)OCH2CH3], 3.85 (dd, J
= 17.6, J = 2.8 Hz, 1 H, NCHAHBCCH), 4.36 (dd, J = 17.6, J =
2.8 Hz, 1 H, NCHAHBCCH), 4.67 (dddd, J = 7.7, J = 4.4, J = 1.1,
4JHP = 1.1 Hz, 1 H, NCH), 5.39 (d, J = 4.4 Hz, 1 H, CHOPh),
(2JCP = 5.8 Hz, HC=CHP), 156.90 (2ϫ Cquat.,arom.), 161.35 (C=O)
ppm. 31P NMR (121 MHz, CDCl ): δ = 18.61 ppm. IR: ν
=
max.
˜
3
1031 (P–O), 1247 (P=O), 1759 (C=O) cm–1. MS (ESI, pos. mode):
m/z (%) = 404 (100) [M + H+]. Chromatography: Hex/EtOAc (1:9)
Rf = 0.22.
Diethyl {(E)-2-[(cis)-1-(2-Bromobenzyl)-4-oxo-3-phenoxyazetidin-2-
yl]vinyl}phosphonate (3f): Yellowish oil (0.80 g, 62%). 1H NMR
1336
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1333–1338

Phosphonobenzocarbacephems by Intramolecular Radical Cyclization
6.06 (ddd, 2JHP = 18.2, J = 18.2, J = 1.1 Hz, 1 H, CHP), 6.69 (ddd, (dd, J = 8.8, J = 4.4 Hz, 1 H, NCH), 4.20 (d, J = 16.5 Hz, 1 H,
3JHP = 20.9, J = 17.1, J = 7.7 Hz, 1 H, HC=CHP), 6.89–6.95 (m, NCHAHBCarom.), 4.76 (d, J = 16.5 Hz, 1 H, NCHAHBCarom.), 4.77
2 H, 2ϫ CHarom.), 7.01 (dd, J = 7.5 Hz, 1 H, CHarom.), 7.22–7.33
(d, J = 11.5 Hz, 1 H, OCHAHBPh), 4.93 (dd, J = 4.4, J = 1.7 Hz,
(m, 2 H, 2ϫ CHarom.) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.28 1 H, CHOPh), 5.01 (d, J = 11.5 Hz, 1 H, OCHAHBPh), 7.09 (psd,
(3JCP = 6.9 Hz, 2ϫ OCH2CH3), 30.29 (NCH2CCH), 59.74 (3JCP
=
=
J = 7.7 Hz, 1 H, CHarom.), 7.19–7.42 (m, 7 H, 7ϫ CHarom.), 7.52
(ps d, = 7.7 Hz, 1 H, CHarom.) ppm. 13C NMR (75 MHz, CDCl3):
δ = 27.74 (1JCP = 140.8 Hz, CH2P), 31.57 (2JCP = 4.6 Hz,
CHCH2P), 40.59 (NCH2Ph), 52.29 [2JCP = 6.9 Hz, P(O)OCH3],
52.52 [2JCP = 6.9 Hz, P(O)OCH3], 54.94 (3JCP = 10.4 Hz, NCH),
73.04 (OCH2Ph), 82.55 (CHOPh), 127.00 (2ϫ CHarom.), 127.55
24.2 Hz, NCH), 61.98 (2JCP = 5.8 Hz, OCH2CH3), 62.06 (2JCP
5.8 Hz, OCH2CH3), 73.70 (NCH2CCH), 75.59 (NCH2CCH), 81.91
(CHOPh), 115.15 (2ϫ CHarom.), 122.54 (CHarom.), 124.53 (1JCP
=
185.8 Hz, CHP), 129.67 (2ϫ CHarom.), 143.70 (2JCP = 5.8 Hz,
HC=CHP), 156.71 (Cquat.,arom.), 164.09 (C=O) ppm. 31P NMR
(121 MHz, CDCl ): δ = 15.77 ppm. IR: ν
= 1021, 1048 (P–O), (CHarom.), 128.10 (2ϫ CHarom.), 128.14 (2ϫ CHarom.), 128.55 (2ϫ
˜
3
max.
1233 (P=O), 1767 (C=O) cm–1. MS (ESI, pos. mode): m/z (%) =
CHarom.), 131.59 (Cquat.,arom.), 135.42 (3JCP = 5.8 Hz, Cquat.,arom.),
137.29 (Cquat.,arom.), 168.56 (C=O) ppm. 31P NMR (121 MHz,
364 (100) [M + H+]. Chromatography: PE/EtOAc (3:7) Rf = 0.11.
CDCl ): δ = 32.34 ppm. IR: νmax. = 1027, 1055 (P–O), 1247 (P=O),
˜
3
Synthesis of Dialkyl {[(1S*,9R*,9aR*)-2-Oxo-1,4,9,9a-tetrahydro-
2H-azeto[1,2-b]isoquinolin-9-yl]methyl}phosphonates 4a–d and Di-
methyl {[(2aR*,8R*,8aS*)-1-Isopropyl-2-oxo-2,2a,8,8a-tetrahydro-
1H-chromeno[3,2-b]azet-8-yl]methyl}phosphonate (4e): As a repre-
sentative example, the synthesis of dimethyl {[(1S*,9R*,9aR*)-2-
oxo-1-phenoxy-1,4,9,9a-tetrahydro-2H-azeto[1,2-b]isoquinolin-9-
yl]methyl}phosphonate (4a) is described here. A solution of di-
methyl {(E)-2-[(cis)-1-(2-bromobenzyl)-4-oxo-3-phenoxyazetidin-2-
yl]vinyl}phosphonate (3a, 0.3 g, 0.607 mmol) in dry toluene
(10 mL) was flushed with Ar for 20 min simultaneously with a
separate solution of Bu3SnH (0.21 g, 0.728 mmol) and AIBN
(0.01 g, 0.061 mmol) in dry toluene (5 mL). The solution of
Bu3SnH and AIBN was slowly added to the stirring solution of β-
lactam 3a at reflux temperature. The reaction could be followed
with 31P NMR and after 6 h, the toluene was evaporated. The
product was dissolved in 10 mL of Et2O and 10 mL of an aqueous
KF solution and then stirred for 30 min. The white solid (Bu3SnF)
could then be filtered off and washed with CH2Cl2. The aqueous
phase was extracted with CH2Cl2 and the combined organic phases
were dried (MgSO4), filtered and the solvents evaporated in vacuo.
The resulting product 4a was purified through column chromatog-
raphy on silica gel (petroleum ether/EtOAc, 1:9) and was isolated
pure in 62% yield (0.15 g).
1754 (C=O) cm–1. MS (ESI, pos. mode): m/z (%) = 402 (100) [M
+ H+]. HRMS (ESI) m/z calcd. for C21H25NO5P [M + H]+
402.1465; found 402.1471. Chromatography: PE/EtOAc (2:8) Rf =
0.30.
Diethyl
{[(1S*,9R*,9aR*)-2-Oxo-1-phenoxy-1,4,9,9a-tetrahydro-
2H-azeto[1,2-b]isoquinolin-9-yl]methyl}phosphonate (4c): Yellowish
oil (0.09 g, 69%). 1H NMR (CDCl3, 300 MHz): δ = 1.18 [t, J =
7.2 Hz, 3 H, P(O)OCH2CH3], 1.23 [t, J = 7.2 Hz, 3 H, P(O)-
2
OCH2CH3], 2.29 (ddd, JHP = 17.9, J = 15.8, J = 6.1 Hz, 1 H,
2
CHAHBP), 2.40 (ddd, JHP = 19.3, J = 15.8, J = 5.0 Hz, 1 H,
CHAHBP), 3.62–3.77 (m, 1 H, CHCH2P), 3.80–4.06 [m, 4 H, 2ϫ
P(O)OCH2CH3], 4.21 (dd, J = 8.8, J = 4.4 Hz, 1 H, NCH), 4.27
(d, J = 16.8 Hz, 1 H, NCHAHBCarom.), 4.82 (d, J = 16.8 Hz, 1 H,
NCHAHBCarom.), 5.51 (dd, J = 4.4, J = 1.7 Hz, 1 H, CHOPh),
7.01–7.37 (m, 8 H, 8ϫ CHarom.), 7.57 (d, J = 7.7 Hz, 1 H, CHarom.
)
ppm. 13C NMR (75 MHz, CDCl3): δ = 16.48 (3JCP = 5.8 Hz, 2ϫ
OCH2CH3), 28.49 (1JCP = 140.8 Hz, CH2P), 31.83 (2JCP = 4.6 Hz,
CHCH2P), 40.78 (NCH2Ph), 54.87 (3JCP = 9.2 Hz, NCH), 61.74
(2JCP = 6.9 Hz, OCH2CH3), 61.88 (2JCP = 6.9 Hz, OCH2CH3),
77.16 (CDCl3), 81.85 (CHOPh), 115.97 (2ϫ CHarom.), 122.49
(CHarom.), 126.95 (CHarom.), 127.03 (CHarom.), 127.55 (CHarom.),
128.31 (CHarom.), 129.73 (2ϫ CHarom.), 131.48 (Cquat.,arom.), 135.08
(3JCP = 5.8 Hz, Cquat.,arom.), 157.75 (Cquat.,arom.), 166.80 (C=O)
ppm. 31P NMR (121 MHz, CDCl ): δ = 29.50 ppm. IR: ν
=
Dimethyl {[(1S*,9R*,9aR*)-2-Oxo-1-phenoxy-1,4,9,9a-tetrahydro-
2H-azeto[1,2-b]isoquinolin-9-yl]methyl}phosphonate (4a): Pale yel-
˜
3
max.
1022, 1052 (P–O), 1233 (P=O), 1757 (C=O) cm–1. MS (ESI, pos.
mode): m/z (%) = 416 (100) [M + H+]. HRMS (ESI) m/z calcd. for
C22H27NO5P [M + H]+ 416.1622; found 416.1632. Chromatog-
raphy: PE/EtOAc (1:2) Rf = 0.14.
1
low oil (0.15 g, 62%). H NMR (CDCl3, 300 MHz): δ = 2.25–2.46
3
(m, 2 H, CH2P), 3.58 [d, JHP = 11.0 Hz, 3 H, P(O)OCH3], 3.65
[d, 3JHP = 11.0 Hz, 3 H, P(O)OCH3], 3.65–3.78 (m, 1 H, CHCH2P),
4.16 (dd, J = 8.5, J = 4.4 Hz, 1 H, NCH), 4.27 (d, J = 16.8 Hz, 1
H, NCHAHBCarom.), 4.82 (d, J = 16.8 Hz, 1 H, NCHAHBCarom.),
5.51 (dd, J = 4.4, J = 1.7 Hz, 1 H, CHOPh), 7.01–7.37 (m, 8 H,
8ϫ CHarom.), 7.55 (d, J = 7.7 Hz, 1 H, CHarom.) ppm. 13C NMR
(75 MHz, CDCl3): δ = 27.73 (1JCP = 141.9 Hz, CH2P), 31.48 (2JCP
= 3.5 Hz, CHCH2P), 40.63 (NCH2), 52.26 [2JCP = 6.9 Hz, P(O)-
OCH3], 52.55 [2JCP = 6.9 Hz, P(O)OCH3], 54.80 (3JCP = 9.2 Hz,
NCH), 81.65 (CHOPh), 115.78 (2ϫ CHarom.), 122.39 (CHarom.),
126.91 (CHarom.), 127.00 (CHarom.), 127.53 (CHarom.), 128.02
(CHarom.), 129.64 (2ϫ CHarom.), 131.37 (Cquat.,arom.), 134.86 (3JCP
= 6.9 Hz, Cquat.,arom.), 157.57 (Cquat.,arom.), 166.59 (C=O) ppm. 31P
Diethyl {[(1S*,9R*,9aR*)-1-Benzyloxy-1,4,9,9a-tetrahydro-2H-2-
oxoazeto[1,2-b]isoquinolin-9-yl]methyl}phosphonate (4d): Pale yel-
1
low oil (0.10 g, 71%). H NMR (CDCl3, 300 MHz): δ = 1.16 [t, J
= 7.2 Hz, 3 H, P(O)OCH2CH3], 1.21 [t, J = 7.2 Hz, 3 H, P(O)
2
OCH2CH3], 2.27 (ddd, JHP = 17.9, J = 16.0, J = 6.1 Hz, 1 H,
2
CHAHBP), 2.34 (ddd, JHP = 18.4, J = 16.0, J = 5.0 Hz, 1 H,
CHAHBP), 3.54–3.69 (m, 1 H, CHCH2P), 3.80–4.06 [m, 5 H, 2ϫ
P(O)OCH2CH3, NCH], 4.18 (d, J = 16.8 Hz, 1 H, NCHAHB-
Carom.), 4.75 (d, J = 16.8 Hz, 1 H, NCHAHBCarom.), 4.79 (d, J =
11.6 Hz, 1 H, OCHAHBPh), 4.91 (dd, J = 4.4, J = 1.7 Hz, 1 H,
CHOPh), 4.99 (d, J = 11.6 Hz, 1 H, OCHAHBPh), 7.08 (ps d, J =
7.2 Hz, 1 H, CHarom.), 7.18–7.42 (m, 7 H, 7ϫ CHarom.), 7.53 (ps
d, J = 7.2 Hz, 1 H, CHarom.) ppm. 13C NMR (75 MHz, CDCl3): δ
= 16.47 (3JCP = 6.9 Hz, 2ϫ OCH2CH3), 28.68 (1JCP = 140.8 Hz,
CH2P), 31.78 (2JCP = 4.6 Hz, CHCH2P), 40.65 (NCH2Ph), 54.97
(3JCP = 9.2 Hz, NCH), 61.72 (2JCP = 6.9 Hz, OCH2CH3), 61.81
NMR (121 MHz, CDCl ): δ = 32.12 ppm. IR: ν
= 1026, 1054
˜
3
max.
(P–O), 1233 (P=O), 1755 (C=O) cm–1. MS (ESI, pos. mode): m/z
(%) = 388 (100) [M + H+], 360 (65) [M+ – 28]. HRMS (ESI) m/z
calcd. for C20H23NO5P [M + H]+ 388.1309; found 388.1314.
Chromatography: PE/EtOAc (1:9) Rf = 0.15.
Dimethyl {[(1S*,9R*,9aR*)-1-Benzyloxy-1,4,9,9a-tetrahydro-2H-2- (2JCP = 6.9 Hz, OCH2CH3), 73.04 (OCH2Ph), 82.63 (CHOPh),
oxoazeto[1,2-b]isoquinolin-9-yl]methyl}phosphonate (4b): Yellow oil
126.90 (CHarom.), 126.97 (CHarom.), 127.47 (CHarom.), 128.10
(CHarom.), 128.14 (2ϫ CHarom.), 128.34 (CHarom.), 128.57 (2ϫ
CHarom.), 131.68 (Cquat.,arom.), 135.63 (3JCP = 5.8 Hz, Cquat.,arom.),
137.38 (Cquat.,arom.), 168.65 (C=O) ppm. 31P NMR (121 MHz,
(0.31 g, 66%). 1H NMR (CDCl3, 300 MHz): δ = 2.21–2.41 (m, 2
3
3
H, CH2P), 3.52 [d, JHP = 11.0 Hz, 3 H, P(O)OCH3], 3.60 [d, JHP
= 11.0 Hz, 3 H, P(O)OCH3], 3.65–3.77 (m, 1 H, CHCH2P), 3.90
Eur. J. Org. Chem. 2010, 1333–1338
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1337

S. Van der Jeught, K. G. R. Masschelein, C. V. Stevens
FULL PAPER
Nakamizo, Agric. Biol. Chem. 1986, 47, 799–806; c) T. Hirata,
A. Sato, N. Nakamizo, Jpn. Kokai Tokkyo Koho 1979, JP
54130596 19791009; d) T. Hirata, A. Sato, N. Nakamizo, Jpn.
Kokai Tokkyo Koho 1979, JP 54130553 19791009; e) G. H.
Hakimelahi, G. Just, Can. J. Chem. 1979, 57, 1939–1944; f)
H. W. Moore, Tetrahedron Lett. 1971, 12, 1621–1624; g) L. M.
Monleon, M. Grande, J. Anaya, Synlett 2007, 1243–1246; h) T.
Gilchrist, A. Rahman, J. Chem. Soc. Perkin Trans. 1 1998,
1203–1208; i) C. Palomo, J. M. Aizpurua, J. M. Garcia, I. Gan-
boa, F. P. Cossio, B. Lecea, C. Lopez, J. Org. Chem. 1990, 55,
2498–2503; j) R. Joyeau, L. D. S. Yadav, M. Wakselman, J.
Chem. Soc. Perkin Trans. 1 1987, 1899–1907; k) R. Joyeau, H.
Molines, R. Labia, M. Wakselman, J. Med. Chem. 1988, 31,
370–374; l) G. Just, G. Sacripante, Can. J. Chem. 1987, 65, 104–
109.
CDCl ): δ = 29.61 ppm. IR: νmax. = 1024, 1053 (P–O), 1243 (P=O),
˜
3
1753 (C=O) cm–1. MS (ESI, pos. mode): m/z (%) = 430 (100) [M
+ H+]. HRMS (ESI) m/z calcd. for C23H29NO5P [M + H]+
430.1778; found 430.1768. Chromatography: PE/EtOAc (3:7) Rf =
0.14.
Dimethyl
{[(2aR*,8R*,8aS*)-1-Isopropyl-2,2a,8,8a-tetrahydro-2-
oxo-1H-chromeno[3,2-b]azet-8-yl]methyl}phosphonate (4e): Yellow
oil (0.50 g, 63%). 1H NMR (300 MHz, CDCl3): δ = 1.13 [d, J =
6.9 Hz, 3 H, CH(CH3)], 1.21 [d, J = 6.9 Hz, 3 H, CH(CH3)], 1.98
2
(ddd, JHP = 18.7, J = 15.7, J = 6.9 Hz, 1 H, NCHCHCHAHB),
2
2.10 (ddd, JHP
= 23.9, J = 15.7, J = 8.3 Hz, 1 H,
NCHCHCHAHB), 3.49–3.58 (m, 1 H, NCHCHCH2), 3.59 (d, 3JHP
= 11.0 Hz, 3 H, OCH3), 3.70 (d, 3JHP = 11.0 Hz, 3 H, OCH3), 3.79
[sept, J = 6.9 Hz, 1 H, CH(CH3)2], 4.45 (dd, J = 5.0, J = 1.7 Hz,
1 H, NCHCHCH2), 5.22 (d, J = 5.0 Hz, 1 H, OCH), 7.01–7.07 (m,
[3] a) J. Finkelstein, K. G. Holden, C. D. Perchonock, Tetrahedron
Lett. 1978, 19, 1629–1632; b) A. K. Bose, B. Ram, N. A. Hoff-
man, A. J. Hutchinson, M. S. Manhas, J. Heterocycl. Chem.
1979, 16, 1313–1316; c) H. Miyake, N. Tokutake, M. Kirisawa,
Synthesis 1983, 833–835; d) M. D. Bachi, J. Klein, J. Chem.
Soc. Perkin Trans. 1 1983, 1925–1928; e) L. S. Hegedus, M. A.
McGuire, L. M. Schultze, C. Yijun, O. P. Anderson, J. Am.
Chem. Soc. 1984, 106, 2680–2687; f) K. H. Ongania, M.
Wallnoefer, Arch. Pharm. (Weinheim, Ger.) 1985, 318, 2–10.
[4] a) S. S. Ng, I. Banik, A. Okawa, F. F. Becker, B. K. Banik, J.
Chem. Res. Synop. 2001, 118–119; b) B. K. Banik, G. V. Subba-
raju, M. S. Manhas, A. K. Bose, Tetrahedron Lett. 1996, 37,
1363–1366; c) S. D. Sharma, S. Kaur, U. Mehra, Indian J.
Chem. Sect. B 1983, 22, 238–242.
2 H, 2ϫ CHarom.), 7.16 (dd, J = 7.7, J = 1.9 Hz, 1 H, CHarom.)
,
7.25 (ddd, J = 8.5, J = 7.4, J = 1.9 Hz, 1 H, CHarom.) ppm. 13C
NMR (75 MHz, CDCl3): δ = 19.89 [CH(CH3)], 21.63 [CH(CH3)],
27.84 (1JCP = 139.6 Hz, NCHCHCH2P), 35.32 (2JCP = 3.5 Hz,
NCHCHCH2P), 44.05 [CH(CH3)2], 52.34 (3JCP = 6.9 Hz, OCH3),
52.45 (3JCP
=
6.9 Hz, OCH3), 59.09 (3JCP
=
10.4 Hz,
NCHCHCH2), 79.88 (OCH), 119.15 (CHarom.), 124.02 (CHarom.)
,
126.59 (3JCP = 10.4 Hz, Cquat.,arom.), 129.56 (CHarom.), 130.00
(CHarom.), 152.31 (Cquat.,arom.), 164.03 (C=O) ppm. 31P NMR
(121 MHz, CDCl ): δ = 32.02 ppm. IR: ν
= 1751 (C=O) cm–1.
max.
˜
3
MS: m/z (%) = (ES, pos.): m/z (%) = 340 (100) [M + H+]. HRMS
(ESI) m/z calcd. for C16H23NO5P [M + H]+ 340.1309; found
340.1313. Chromatography: EtOAc/MeOH (95:5) Rf = 0.25.
[5] a) C. Stevens, M. Gallant, N. De Kimpe, Tetrahedron Lett.
1999, 40, 3457–3460; b) B. Vanderhoydonck, C. V. Stevens,
Synthesis 2004, 5, 722–734; c) B. Vanderhoydonck, C. V. Ste-
vens, J. Org. Chem. 2005, 70, 191–198.
[6] a) K. G. R. Masschelein, C. V. Stevens, J. Org. Chem. 2007, 72,
9248–9252; b) K. G. R. Masschelein, C. V. Stevens, Tetrahedron
Lett. 2008, 49, 4336–4338.
Acknowledgments
[7] a) C. E. Griffin, S. K. Kundu, J. Org. Chem. 1969, 34, 1532–
1539; b) G. Just, P. Potvin, G. H. Hakimelahi, Can. J. Chem.
1980, 58, 2780–2783.
S. V. d. J. wishes to thank the Fund for Scientific Research Flanders
(FWO Vlaanderen) for financial support.
[8] a) P. A. Baguley, J. C. Walton, Angew. Chem. 1998, 110, 3072–
3082; b) A. Parsons, Chem. Br. 2002, 38, 42–44.
[1] G. Veinberg, M. Vorona, I. Shestakova, I. Kanepe, E. Lukevics,
Curr. Med. Chem. 2003, 10, 1741.
[2] a) B. Alcaide, P. Almendros, A. Rodríguez-Vicente, M. P. Ruiz,
Tetrahedron 2005, 61, 2767–2778; b) A. Sato, T. Hirata, N.
[9] J. E. Leibner, J. Jacobus, J. Org. Chem. 1979, 44, 449–450.
Received: November 23, 2009
Published Online: January 28, 2010
1338
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Eur. J. Org. Chem. 2010, 1333–1338