Synthesis of 1-hydroxypyrrolidin-2,5-dione derivatives of the phosphonic-hydroxamic acid antibiotic SF-2312

Article abstract of DOI:10.1071/CH06058

Analogues of the antibiotic SF-2312 with a 3-substituted 1-hydroxypyrrolidine moiety have been prepared from 1-benzyloxy-3- bromopyrrolidin-2,5-dione (1) through Michaelis-Arbusov reaction with various trialkyl phosphites and subsequent alkylation of ring

Full text of DOI:10.1071/CH06058

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2006, 59, 283–288
Synthesis of 1-Hydroxypyrrolidin-2,5-dione Derivatives
of the Phosphonic–Hydroxamic Acid Antibiotic SF-2312
Wamuyu Owotoki,A Detlef Geffken,A and Thomas KurzA,B
A Institute of Pharmacy, University of Hamburg, 20146 Hamburg, Germany.
B Corresponding author. Email: kurz@chemie.uni-hamburg.de
Analogues of the antibiotic SF-2312 with a 3-substituted 1-hydroxypyrrolidine moiety have been prepared from
1-benzyloxy-3-bromopyrrolidin-2,5-dione (1) through Michaelis–Arbusov reaction with various trialkyl phosphites
and subsequent alkylation of ring position 3. Cleavage of phosphonic esters 3 byTMSBr afforded the corresponding
phosphonic acids 7, which were treated with ethanolamine to give the monosalts 8. Finally, hydrogenolysis furnished
1-hydroxypyrrolidin-2,5-diones 9.
Manuscript received: 21 February 2006.
Final version: 12 April 2006.
Introduction
Michaelis–Arbusov reaction of 1 with various alkyl phos-
phites provided the phosphonic esters 2a–2c in 63–77%
yields.
Alkylation of compounds 2a–2c with alkyl(benzyl)
halides in presence of sodium hydride afforded
3-substituted 1-benzyloxypyrrolidin-2,5-diones (3a–3j) in
51–91% yields.[12] Catalytic hydrogenation of 3a–3f pro-
vided N-hydroxyimides (4a–4f) in yields of 52–85% as solid
compounds.
Compounds containing both the hydroxamic acid and phos-
phonic acid functions have attracted growing interest in
medicinal chemistry because of their broad antimicrobial
spectra.[1,2] In 1986, Watabe et al. reported the isola-
tion of the novel broad spectrum antibiotic SF-2312 from
Micromonospora sp.,[3] which is characterized by a cyclic
N-hydroxyimide and a phosphonic acid functionality.[4] In a
formal sense SF-2312 might be regarded as a rigid analogue
of the open-chain antibiotic Fosmidomycin (Fig. 1) which
displays its antimicrobial activity through the inhibition of
the non-mevalonate synthesis of isoprenoids by blocking the
DOXP-reductoisomerase.[5–9]
On account of the good antibacterial activities of
SF-2312 and Fosmidomycin, we became interested in inves-
tigating the structure–activity relationship of SF-2312. We
report herein the synthesis and properties of 3-substituted
1-hydroxypyrrolidin-2,5-dione analogues of SF-2312.
Treatment of 4f with 4-methoxyphenyl-isocyanate led to
the carbamate 5 in 84% yield (Scheme 1, Table 1).
Functionalization of the pyrrolidin-2,5-dione nucleus was
also achieved through Mannich reaction of 2a with forma-
lin and piperidine in acetic acid.[13] The Mannich base was
isolated as a crystalline hydrogen chloride salt (6; Scheme 2)
which has also been characterized by X-ray crystallography.
Cleavage of the phosphonic acid esters 3f–3j by
trimethylsilyl bromide led to the phosphonic acids 7a–7e as
highly hygroscopic compounds that did not furnish satisfac-
tory elemental analysis data.[14] With regard to the reported
stability of phosphonic acid ethanolamine salts,[15] we treated
7a–7e with ethanolamine in a molar ratio of 1:0.9 in dry
tetrahydrofuran. After subsequent cooling at −18◦C for two
days, the monosalts 8a–8e were obtained as analytically
pure compounds in yields of 57–68% (Scheme 3, Table 2).
Finally, catalytic hydrogenation of 8a–8e provided 9a–9e in
high yields of 90–96% as stable compounds. The IR spec-
tra of compounds 8 show two carbonyl bands at 1706–1724
and 1782–1786 cm−1 whereas the 1-hydroxypyrrolidin-2,5-
diones 9 exhibit the carbonyl bands bathochromically shifted
to 1697–1718 and 1774–1782 cm−1. All compounds were
Results and Discussion
The starting material 1-benzyloxy-3-bromopyrrolidin-2,5-
dione (1) was prepared by bromination of N-benzyloxyiso-
maleimide[10] according to the literature procedure.[11]
O
O
O
R
NaO
HO
P
HO
HO
P
HO
HO
P
N
N
N
O
OH
O
O
O
OH
OH
OH
SF-2312
Target compound
Fosmidomycin
1
characterized by elemental analysis and IR, H NMR, and
13C NMR spectroscopy.
Fig. 1.
© CSIRO 2006
10.1071/CH06058
0004-9425/06/040283

284
W. Owotoki, D. Geffken, and T. Kurz
O
O
O
O
1
1
R
R1
N
RO
RO
P
R
Br
O
HO
HO
P
EtO
EtO
P
RO
RO
P
(b)
(b)
(a)
(a)
N
N
O
O
O
N
O
O
N
O
O
O
O
OB
OBn
OBn
OBn
OBn
3a–3j
2a: R=Et,
2b: R=Me,
2c: R=Pri
1
3f–3j
7a–7e
(c)
O
O
1
1
OϪ
HO
OϪ
R
NHϩ3
NHϩ3
R
P
P
O
(c)
O
HO
EtO
EtO
P
R1
RO
RO
P
O
N
N
O
O
O
O
OH
OH
(d)
N
O
O
OH
9a–9e
OBn
N
O
O
O
8a–8e
N
OH
H
O
Scheme 3. Synthesis of compounds 7–9. (a) (1) TMSBr, (2) H2O;
(b) H2NCH2CH2OH/THF or MeOH; (c) H2/Pd-C.
5
4a–4f
Scheme 1. Synthesis of 3-substituted 1-hydroxypyrrolidin-2,5-diones
4. (a) P(OEt)3, P(OMe)3, or P(OPri)3; (b) NaH, R1Br or R1I;
(c) H2/Pd-C; (d) 4-MeO-PhNCO.
Table 2. Synthesis of compounds 8 and 9
8, 9
R1
Yields [%]
8
9
Table 1. Synthesis of compounds 3 and 4
a
b
c
d
e
Bn
4-F-Bn
4-Me-Bn
CH2=CH–CH2
4-MeO-Bn
57
68
65
64
66
96
90
90
92A
96
3, 4
R
R1
Yields [%]
3
4
a
b
c
d
e
f
g
h
i
Me
Pri
Pri
Et
Et
Et
Et
Et
Et
Et
Bn
4-F-Bn
Bn
Me
3-PhO-Bn
Bn
4-F-Bn
4-Me-Bn
CH2=CH–CH2
4-MeO-Bn
91
78
70
60
68
80
64
78
71
51
82
85
85
76
52
69
–
–
–
–
A R1 = n-C3H7.
Experimental
General
Melting points were determined on a Mettler FP 62 apparatus and are
uncorrected. Elemental analyses were carried out with a Heraeus CHN-
O-Rapid instrument. IR spectra were recorded on a Shimadzu FT-IR
8300 or a Perkin–Elmer Series 1600 FT-IR. 1H NMR (400.14 MHz) and
13C NMR (100.61 MHz) spectra were recorded on a Bruker AMX 400
spectrometer using tetramethylsilane (δ 0.00) as the internal standard
and [D6]DMSO, D2O, or CDCl3 as solvents. Coupling constants are
reported in Hertz. Column chromatography was conducted on silica gel
(ICN silica 100–200, active 60 Å).
j
Nϩ
H
O
O
H
N
EtO
EtO
P
EtO
EtO
P
ClϪ
,
HCHO
HCl(g)
N
N
O
O
O
O
General Procedure for the Preparation of 2a–2c
OBn
OBn
1-Benzyloxy-3-bromopyrrolidin-2,5-dione (1; 0.57 g, 2 mmol) was
refluxed at 140◦C with the respective trialkyl phosphite (12 mmol) for
2 h. Excess of trialkyl phosphite was removed in vacuo and the oily
residue was purified by column chromatography. Elution with EtOAc/
n-hexane (4/1) afforded oily compounds, which in the case of 2a and
2b furnished solids compounds after drying for 5 min in vacuo.
2a
6
Scheme 2.
Conclusions
This paper describes a simple and effective synthetic route
for the preparation of novel 1-hydroxy-pyrrolidin-2,5-dione
analogues of the phosphonic acid antibiotic SF-2312. Due
to their hygroscopicity the phosphonic acids have been con-
verted into stable, non-hygroscopic ethanolamine monosalts.
In the course of further investigations the selective reduction
of the carbonyl groups of the pyrrolidin-2,5-dione nucleus is
intended.The results of the biological studies will be reported
in due course.
Diethyl (1-Benzyloxy-2,5-dioxopyrrolidin-3-yl)phosphonate 2a
Light green solid (77%), mp 88◦C. (Found: C 52.97, H 5.99, N 4.09%.
C15H20NO6P requires C 52.79, H 5.91, N 4.10%.) νmax (KBr)/cm−1
1782, 1724 (C=O), 1251 (P=O), 1016 (POC). δH (CDCl3) 7.49–7.40
(m, 5H, ArH), 5.00 (s, 2H, CH2Ph), 4.13–4.05 (m, 4H, POCH2), 3.74–
3.65 (m, 1H, PCH), 3.08–2.99 (m, 1H, CH2), 2.69–2.66 (m, 1H, CH2),
1.23–1.27 (m, 6H, (CH3)2). δC (CDCl3) 169.1, 166.6 (C=O), 133.2
(ArCquart.), 128.6, 129.5, 129.9 (ArCtert.), 78.9 (CH2Ph), 63.4 (d, 2JC,P
6.61, POC), 63.9 (d, 2JC,P 7.12, POC), 36.9 (d, 1JC,P 142.9, PCH), 27.9
(CH2), 16.4 (t, 3JC,P 5.10, CH3).

Synthesis of Derivatives of the Antibiotic SF-2312
285
Dimethyl (1-Benzyloxy-2,5-dioxopyrrolidin-3-yl)phosphonate 2b
(CDCl3) 170.6, 169.5 (C=O), 134.3, 133.8 (ArCquart.), 130.7, 130.1,
129.7, 129.5, 128.9, 128.8 (ArCtert.), 79.4 (CH2Ph), 73.5 (d, 2JC,P 7.12,
POC), 73.1 (d, 2JC,P 7.63, POC), 48.2 (d, 1JC,P 139.88, PC), 36.5 (CH2),
31.9 (CH2), 24.6 (d, 3JC,P 3.05, CH3), 24.5 (d, 3JC,P 4.07, CH3), 24.2
(d, 3JC,P 5.59, CH3), 24.1 (d, 3JC,P 6.11, CH3).
White solid (64%), mp 85◦C. (Found: C 49.51, H 5.20, N 4.48%.
C13H16NO6P requires C 49.85, H 5.15, N 4.47%.) νmax (KBr)/cm−1
1787, 1728 (C=O), 1257 (P=O), 1031 (POC). δH ([D6]DMSO) 7.49–
7.40 (m, 5H, ArH), 5.01 (s, 2H, CH2Ph), 3.70–3.62 (m, 4H, POCH2),
3.08–2.98 (m, 1H, PCH), 2.76–2.74 (m, 1H, CH2), 3.81–3.76 (m, 1H,
CH2). δC ([D6]DMSO) 169.9, 167.3 (C=O), 134.1 (ArCquart.), 129.9,
129.5, 128.8 (ArCtert.), 78.5 (CH2Ph), 54.0 (d, 2JC,P 6.61, POC), 53.7
(d, 2JC,P 6.62, POC), 35.9 (d, 1JC,P 140.39, PC), 27.9 (CH2).
Diethyl (1-Benzyloxy-3-methyl-2,5-dioxopyrrolidin-
3-yl)phosphonate 3d
White solid (60%), mp 54◦C. (Found: C 53.76, H 6.30, N 3.90%.
C16H22NO6P requires C 54.08, H 6.24, N 3.94%.) νmax (KBr)/cm−1
1784, 1732 (C=O), 1247 (P=O), 1020 (POC). δH (CDCl3) 7.42–7.38
(m, 5H, ArH), 5.01 (ABs, 2H, CH2Ph), 4.04 (m, 4H, POCH2), 2.76–
2.71 (m, 2H, CH2), 1.25–1.23 (m, 6H, (CH3)2), 1.44 (d, J 16.53, 3H,
CH3). δC (CDCl3) 170.6, 168.9 (C=O), 133.7 (ArCquart.), 129.4, 129.0,
Diisopropyl (1-Benzyloxy-2,5-dioxopyrrolidin-3-yl)phosphonate 2c
Yellow oil (63%). (Found: C 55.26, H 6.57, N 3.50%. C17H24NO6P
requires C 55.28, H 6.55, N 3.79%.) νmax (film)/cm−1 1799, 1739
(C=O), 1261 (P=O), 999 (POC). δH (CDCl3) 7.52–7.37 (m, 5H, ArH),
5.08 (s, 2H, CH2Ph), 4.82–4.74 (m, 2H, POCH), 3.21–3.12 (m, 1H, CH),
2.99–2.81 (m, 2H, CH2), 1.38–1.33 (m, 12H, CH3). δC (CDCl3) 169.7,
167.1 (C=O), 133.6 (ArCquart.), 130.7, 130.3, 129.8, 128.9 (ArCtert.),
79.3 (CH2Ph), 73.2 (d, 2JC,P 6.61, POC), 72.8 (d, 2JC,P 6.61, POC), 37.7
2
128.4 (ArCtert.), 78.0 (OCH2Ph), 63.3 (d, JC,P 7.12, POC), 63.5 (d,
2JC,P 6.61, POC), 41.7 (d, 1JC,P 139.90, PC), 35.5 (CH2), 17.6 (d, 2JC,P
4.07, CH3), 16.3 (d, 3JC,P 5.09, CH3).
Diethyl [1-Benzyloxy-3-(3-phenoxybenzyl)-2,5-dioxopyrrolidin-
3-yl]phosphonate 3e
1
3
(d, JC,P 142.42, PC), 28.3 (CH2), 24.5 (d, JC,P 3.07, CH3), 24.4 (d,
3JC,P 4.07, CH3), 24.2 (t, 3JC,P 5.83, CH3).
Colourless oil (68%). (Found: C 64.35, H 6.13, N 2.44%. C28H30NO7P
requires C 64.24, H 5.78, N 2.68%.) νmax (film)/cm−1 1789, 1724
(C=O), 1252 (P=O), 1018 (POC). δH ([D6]DMSO) 7.37–6.93 (m, 14H,
ArH), 4.75 (ABs, J 4.83, CH2Ph), 4.17–4.10 (m, 4H, POCH2), 3.45–
3.39 (m, 1H, CH2), 3.03–2.80 (m, 3H, CH2), 1.25 (t, J 7.42, 6H, CH3).
δC ([D6]DMSO) 170.0, 168.9 (C=O), 156.9, 136.4, 133.8 (ArCquart.),
130.7, 130.4, 129.9, 128.8, 125.9, 123.3, 120.9, 118.9 (ArCtert.), 78.7
(CH2Ph), 63.5 (d, 2JC,P 7.12, POC), 63.8 (d, 2JC,P 7.12, POC), 47.5 (d,
1JC,P 139.90, PC), 35.9 (CH2), 31.9 (CH2), 16.6 (d, 3JC,P 5.30, CH3).
General Procedure for the Preparation of 3a–3j
To a stirred solution of 2a–2c (2 mmol) in dry THF (5 mL) under
N2 atmosphere was added sodium hydride (0.05 g, 2 mmol) portion-
wise over a period of 10 min. After stirring for 10 min, a solution of
the appropriate alkyl(benzyl) halide (2 mmol) in dry THF (2 mL) was
added dropwise. The reaction mixture was stirred for 90 min, poured
into ice-cold 1 M HCl solution and extracted with EtOAc (3 × 10 mL).
The combined organic layers were washed with brine (10 mL), dried
over MgSO4, and evaporated. The oily residues were purified by col-
umn chromatography (3/2 EtOAc/n-hexane elution) to give 3a–3j as oily
or solid compounds. Compounds 3a, 3b, 3d, 3f–3h were crystallized
from EtOAc/n-hexane.
Diethyl (3-Benzyl-1-benzyloxy-2,5-dioxopyrrolidin-3-yl)-
phosphonate 3f
Yellow oil (80%). (Found: C 61.06, H 6.22, N 3.08%. C22H26NO6P
requires C 61.25, H 6.07, N 3.25%.) vmax (film)/cm−1 1787, 1726
(C=O), 1249 (P=O), 1018 (POC). δH (CDCl3) 7.38–7.23 (m, 10H,
ArH), 4.64 (ABs, J 46.36, 2H, CH2Ph), 4.20–4.12 (m, 4H, POCH2),
3.49–3.44 (m, 1H, CH2), 3.01–2.77 (m, 3H, CH2), 1.28 (dt, J 1.78,
J 7.09, 6H, (CH3)2). δC (CDCl3) 170.0, 168.8 (C=O), 134.2, 133.8
(ArCquart.), 130.7, 129.9, 129.5, 129.1, 128.8, 128.0 (ArCtert.), 78.6
(CH2Ph), 64.0 (d, 2JC,P 7.12, POC), 63.8 (d, 2JC,P 6.61, POC), 47.6 (d,
1JC,P 139.88, PC), 36.1 (CH2), 31.7 (CH2), 16.6 (d, 3JC,P 5.08, CH3).
Dimethyl (3-Benzyl-1-benzyloxy-2,5-dioxopyrrolidin-
3-yl)phosphonate 3a
White solid (91%), mp 78.8◦C. (Found: C 59.53, H 5.52, N 3.30%.
C20H22NO6P requires C 59.55, H 5.50, N 3.47%.) νmax (KBr)/cm−1
1789, 1724 (C=O), 1258 (P=O), 1014 (POC). δH (CDCl3) 7.41–7.13
(m, 10H,ArH), 4.83 (ABs, J 14.00, CH2Ph), 3.89 (t, J 10.93, 6H, CH3),
3.69–3.66 (m, 1H, CH2), 3.05–2.93 (m, 2H, CH2), 2.65–2.63 (m, 1H,
CH2). δC (CDCl3) 170.4, 168.9 (C=O), 133.9, 133.7 (ArCquart.), 130.7,
130.2, 129.7, 129.5, 128.9, 128.5 (ArCtert.), 79.4 (CH2Ph), 55.6 (d, 2JC,P
7.12, POC), 55.7 (d, 2JC,P 7.12, POC), 48.1 (d, 1JC,P 140.89, PC), 36.6
(CH2), 31.8 (CH2).
Diethyl [1-Benzyloxy-3-(4-fluorobenzyl)-2,5-dioxopyrrolidin-
3-yl]phosphonate 3g
White solid (64%), mp 66◦C. (Found: C 58.90, H 5.61, N 3.19%.
C22H25FNO6P requires C 58.80, H 5.61, N 3.12%.) νmax (KBr)/cm−1
1786, 1726 (C=O), 1251 (P=O), 1018 (POC). δH (CDCl3) 7.40–6.97
(m, 9H, ArH), 4.92–4.85 (m, 2H, CH2Ph), 4.26–4.24 (m, 4H, POCH2),
3.68–3.63 (m, 1H, CH2), 3.06–2.93 (m, 2H, CH2), 2.62–2.54 (m, 1H,
CH2), 1.36 (t, J 6.94, 6H, (CH3)2). δC (CDCl3) 170.0, 168.6 (C=O),
162.2 (d, JC,F 247.60, CF), 133.2, 129.5 (ArCquart.), 131.9, 129.7, 128.5,
116.1 (ArCtert.), 78.93 (CH2Ph), 64.3 (d, 2JC,P 6.61, POC), 64.0 (d, 2JC,P
Diisopropyl [3-(4-Flurobenzyl)-1-benzyloxy-2,5-dioxopyrrolidin-
3-yl]phosphonate 3b
Rod-like crystals (78%), mp 83.8◦C. (Found: C 60.33, H 6.26, N 2.91%.
C24H29NO6P requires C 60.37, H 6.12, N 2.93%.) νmax (KBr)/cm−1
1787, 1731 (C=O), 1249 (P=O), 975 (POC). δH (CDCl3) 7.42–6.95
(m, 9H, ArH), 4.92–4.86 (m, 2H, CH2Ph), 4.85–4.77 (m, 2H, POCH),
3.65–3.63 (m, 1H, CH2), 3.03–2.87 (m, 2H, CH2), 2.56–2.64 (m, 1H,
CH2), 1.41–1.35 (m, 12H, CH3). δC 170.4, 169.3 (C=O), 162.7 (d,
JC,F 247.19, CF), 133.6 (ArCquart.), 132.3, 130.1, 129.70, 128.9, 116.5
(ArCtert.), 79.3 (CH2Ph), 73.6 (d, 2JC,P 7.12, POC), 73.2 (d, 2JC,P 7.63,
POC), 48.2 (d, 1JC,P 139.87, PC), 35.6 (CH2), 31.9 (CH2), 24.6 (d, 3JC,P
1
7.63, POC), 47.8 (d, JC,P 141.47, PC), 35.2 (CH2), 31.4 (CH2), 16.5
(t, 3JC,P 5.85, CH3).
Diethyl [1-Benzyloxy-3-(4-methylbenzyl)-2,5-dioxopyrrolidin-
3-yl]phosphonate 3h
White solid (78%), mp 54◦C. (Found C 61.85, H 6.35, N 3.20%.
C23H28NO6P requires C 62.02, H 6.34, N 3.14%.) νmax (KBr)/cm−1
1782, 1720 (C=O), 1257 (P=O), 1020 (POC). δH (CDCl3) 7.40–7.01
(m, 9H, ArH), 4.87 (ABs, J 27.15, 2H, CH2Ph), 4.28–4.17 (m, 4H,
POCH2), 3.69–2.64 (m, 1H, CH2), 3.03–2.88 (m, 2H, CH2), 2.67–
2.60 (m, 1H, CH2), 2.29 (s, 3H, CH3), 1.42–1.34 (m, 6H, (CH3)2). δC
(CDCl3) 170.2, 168.9 (C=O), 137.7, 133.4 (ArCquart.), 130.1, 129.7,
129.3, 128.5 (ArCtert.), 78.92 (CH2Ph), 133.7 (ArCquart.), 129.4, 129.0,
3
3
3.05, CH3), 24.5 (d, JC,P 4.07, CH3), 24.3 (d, JC,P 5.09, CH3), 24.1
(d, 3JC,P 6.10, CH3).
Diisopropyl (3-Benzyl-1-benzyloxy-2,5-dioxopyrrolidin-
3-yl)phosphonate 3c
Colourless oil (70%). (Found: C 62.63, H 6.78, N 2.97%. C24H30NO6P
requires C 62.74, H 6.58, N 3.05%.) νmax (film)/cm−1 1789, 1728
(C=O), 1261 (P=O), 989 (POC). δH (CDCl3) 7.40–7.13 (m, 10H,
ArH), 4.87–4.77 (m, 2H, POCH), 3.70–3.69 (m, 1H, CH2), 3.02–2.89
(m, 2H, CH2), 2.62–2.60 (m, 1H, CH2), 1.42–1.35 (m, 12H, CH3). δC
2
128.4 (ArCtert.), 78.0 (OCH2Ph), 63.9 (d, JC,P 7.12, POC), 64.1
(d, 2JC,P 6.61, POC), 47.6 (d, 1JC,P 139.37, PC), 35.7 (CH2), 31.4 (CH2),
21.0 (CH3), 16.4 (t, 3JC,P 5.85, CH3).

286
W. Owotoki, D. Geffken, and T. Kurz
Diethyl (3-Allyl-1-benzyloxy-2,5-dioxopyrrolidin-
3-yl)phosphonate 3i
169.5 (C=O), 134.2 (ArCquart.), 130.5, 129.3, 128.2 (ArCtert.), 75.3 (d,
2JC,P 7.12, POC), 73.3 (d, 2JC,P 7.63, POC), 47.9 (d, 1JC,P 144.45, PC),
37.3 (CH2), 31.4 (CH2), 24.9 (d, 3JC,P 1.52, CH3), 24.3 (d, 3JC,P 3.56,
CH3), 24.2 (d, 3JC,P 5.08, CH3), 23.8 (d, 3JC,P 7.12, CH3).
Colourless oil (71%). (Found: C 56.76, H 6.54, N 3.72%. C18H24NO6P
requires C 56.69, H 6.50, N 3.67%.) νmax (KBr)/cm−1 1789, 1728
(C=O), 1249 (P=O), 1018 (POC). δH (CDCl3) 7.51–7.37 (m, 5H,ArH),
5.38–5.28 (m, 1H, CH2CH), 5.19–5.15 (m, 2H, CH2CH), 5.10 (ABs,
J 12.86, 2H, CH2Ph), 4.22–4.16 (m, 4H, POCH2), 3.04–2.87 (m, 2H,
CH2), 2.65–2.58 (m, 1H, CH2), 2.46–2.39 (m, 1H, CH2), 1.38–1.31
(m, 6H, (CH3)2). δC (CDCl3) 169.9, 169.2 (C=O), 133.3 (ArCquart.),
129.7, 129.4, 128.5 (ArCtert.), 122.1 (CH2), 78.7 (OCH2Ph), 63.7 (d,
Diethyl (1-Hydroxy-3-methyl-2,5-dioxopyrrolidin-
3-yl)phosphonate 4d
White solid (76%), mp 118◦C. (Found: C 40.76, H 6.08, N 5.25%.
C9H16NO6P requires C 40.76, H 6.08, N 5.28%.) νmax (KBr)/cm−1
1782, 1720 (C=O), 1230 (P=O), 1014 (POC). δH (CDCl3) 4.26–4.18
(m, 4H, POCH2), 3.20–2.47 (m, 2H, CH2), 1.44 (d, J 16.53, 3H, CH3)/
1.23–1.26 (m, 6H, (CH3)2). δC (CDCl3) 171.4, 169.7 (C=O), 65.4
(d, 2JC,P 6.61, POC), 63.6 (d, 2JC,P 7.63, POC), 41.9 (d, 1JC,P 147.50,
PC), 35.9 (CH2), 31.9 (CH2), 19.7 (d, 3JC,P 4.98, CH3), 16.3 (d, 3JC,P
5.93, CH3).
2
1
2JC,P 6.61, POC), 64.0 (d, JC,P 7.12, POC), 45.6 (d, JC,P 139.96,
PC), 35.4 (CH2), 31.9 (CH2), 16.4 (d, 3JC,P 5.08, CH3), 16.5 (d, 3JC,P
6.11, CH3).
Diethyl [1-Benzyloxy-3-(4-methoxybenzyl)-2,5-dioxopyrrolidin-
3-yl]phosphonate 3j
Diethyl [1-Hydroxy-3-(3-phenoxybenzyl)-2,5-dioxopyrrolidin-
3-yl]phosphonate 4e
Yellow oil (51%). (Found: C 59.52, H 6.34, N 2.95%. C23H28NO6P
requires C 59.87, H 6.12, N 3.04%.) νmax (KBr)/cm−1 1791, 1726,
(C=O), 1251 (P=O), 1018 (POC). δH (CDCl3) 7.41–6.79 (m, 9H,ArH),
4.85 (ABs, J 23.46, 2H, CH2Ph), 4.28–4.17 (m, 4H, POCH2), 3.75 (s,
3H, OCH3), 3.67–3.62 (m, 1H, CH2), 3.03–2.86 (m, 2H, CH2), 2.67–
2.60 (m, 1H, CH2), 1.45–1.34 (m, 6H, (CH3)2). δC (CDCl3) 170.4,
168.9 (C=O), 159.3, 133.4, 125.5 (ArCquart.), 131.3, 129.8, 129.3,
128.5, 114.4 (ArCtert.), 78.9 (CH2Ph), 63.9 (d, 2JC,P 7.12, POC), 64.1 (d,
2JC,P 6.61, POC), 55.3 (OCH3), 35.7 (CH2), 31.4 (CH2), 16.5 (t, 3JC,P
5.85, CH3).
White solid (52%), mp 174.4◦C. (Found: C 57.85, H 5.76, N 3.17%.
C21H24NO7P requires C 58.20, H 5.58, N 3.23%.) νmax (KBr)/cm−1
1787, 1723 (C=O), 1254 (P=O), 971 (POC). δH (CDCl3) 9.37 (s, 1H,
OH), 7.35–6.76 (m, 9H, ArH), 4.36–4.19 (m, 4H, POCH2), 3.63–3.60
(m, 1H, CH2), 2.99–2.93 (m, 1H, CH2), 2.82–2.79 (m, 1H, CH2), 2.58–
2.55 (m, 1H, CH2), 1.39–1.36 (m, 6H, (CH3)2). δC (CDCl3) 171.6,
169.6 (C=O), 158.1, 152.3 (ArCquart.), 125.1, 123.9, 120.8, 119.4, 118.6
2
2
(ArCtert.), 65.9 (d, JC,P 6.61, POC), 64.0 (d, JC,P 7.63, POC), 47.8
(d, 1JC,P 142.42, PC), 36.8 (CH2), 31.3 (CH2), 16.7 (q, 3JC,P 5.76, CH3).
General Procedure for the Preparation of 4a–4f
Diethyl (1-Hydroxy-3-benzyl-2,5-dioxopyrrolidin-
3-yl)phosphonate 4f
Compounds 3a–3f (5 mmol) were dissolved in MeOH (100 mL), Pd-C
10% (300 mg) was added and the resulting mixture was hydrogenated
for 90 min. The suspension was filtered through an SPE tube RP-18.
The solvent was evaporated and the residue crystallized from EtOAc/
n-hexane to give 4a–4f.
White solid (69%), mp 162◦C. (Found: C 52.37, H 5.97, N 3.91%.
C15H20NO6P requires C 52.79, H 5.91, N 4.10%.) vmax (KBr)/cm−1
1786, 1724 (C=O), 1242 (P=O), 1026 (POC). δH (CDCl3) 7.11–7.04
(m, 5H, ArH), 4.22–4.19 (m, 4H, POCH2), 3.64–3.61 (m, 2H, CH2),
2.96–2.86(m, 2H, CH2), 2.58–2.56(m, 2H, CH2), 1.38(m, 6H, (CH3)2).
δC (CDCl3) 170.9, 169.8 (C=O), 133.9 (ArCquart.), 130.5, 129.4, 128.3
Dimethyl (3-Benzyl-1-hydroxy-2,5-dioxopyrrolidin-
3-yl)phosphonate 4a
2
2
White solid (82%), mp 198.8◦C. (Found: C 49.55, H 5.13, N 4.46%.
C13H16NO6P requires C 49.85, H 5.15, N 4.47%.) νmax (KBr)/cm−1
1783, 1724 (C=O), 1227 (P=O), 1039 (POC). δH (CDCl3) 9.58 (s, 1H,
OH), 7.28–7.08 (m, 5H,ArH), 3.99 (d, J 10.93, OCH3), 3.85 (d, J 10.93,
3H, OCH3), 3.65–3.62 (m, 1H, CH2), 2.98–2.96 (m, 1H, CH2), 2.89–
2.85 (m, 1H, CH2), 2.59–2.54 (m, 1H, CH2). δC 170.7, 169.5 (C=O),
(ArCtert.), 66.1 (d, JC,P 7.12, POC), 64.1 (d, JC,P 7.63, POC), 47.8
(d, 1JC,P 143.4, PC), 37.1 (CH2), 31.3 (CH2), 16.8 (q, 3JC,P 6.60, CH3).
Diethyl [3-Benzyl-1-({[(4-methyoxyphenyl)amino]carbonyl}oxy)-
2,5-dioxopyrrolidin-3-yl]phosphonate 5
To a solution of 4a (0.11 g, 0.32 mmol) in dry DCM (3 mL) was added
4-methoxy-phenylisocyanate (0.48 g, 0.32 mmol). After stirring for 48
h, the solvent was evaporated and the crude product crystallized in
Et2O/n-hexane to yield compound 5 as short, white needles (0.138 g,
84%), mp 153.5◦C. (Found: C 56.30, H 5.42, N 5.83%. C23H27N2O8P
requires C 56.33, H 5.55, N 5.71%.) νmax (KBr)/cm−1 1779, 1739
(C=O), 1248 (P=O), 1017 (POC). δH (CDCl3) 7.32–7.16 (m, 7H,ArH),
7.00 (s, 1H, NH), 6.87–6.85 (m, 2H, ArH), 4.31–4.25 (m, 4H, OCH2),
3.79 (m, 1H, OCH3), 3.78–3.73 (m, 1H, CH2), 3.17–3.02 (m, 1H, CH2),
2.79–2.72 (m, 1H, CH2), 1.41 (t, J 7.01, 3H, CH3), 1.37 (t, J 3.76, 3H,
CH3). δC (CDCl3) 169.5, 167.9, 148.7 (C=O), 133.9, 133.8 (ArCquart.),
130.6, 129.4, 128.4, 121.6, 114.8 (ArCtert.), 64.8 (d, 2JC,P 7.12, POC),
64.6 (d, 2JC,P 7.12, POC), 55.9 (OCH3), 48.4 (d, 1JC,P 140.40, PC), 36.7
(CH2), 31.9 (CH2), 16.8 (q, 3JC,P 5.43, CH3).
2
133.5 (ArCquart.), 130.4, 129.5, 128.4 (ArCtert.), 56.3 (d, JC,P 6.62,
POC), 54.1 (d, 2JC,P 7.63, POC), 48.7 (PC), 31.3 (CH2), 30.1 (CH2).
Diisopropyl [3-(4-Flurobenzyl)-1-hydroxy-2,5-dioxopyrrolidin-
3-yl]phosphonate 4b
White solid (85%), mp 180.2◦C. (Found: C 51.82, H 5.92, N 3.58%.
C17H23FNO6P·1/2H2O requires C 51.52, H 6.10, N 3.53%.) νmax
(KBr)/cm−1 1790, 1724 (C=O), 1245 (P=O), 990 (POC). δH (CDCl3)
9.91 (s, 1H, OH), 7.08–6.94 (m, 4H, ArH), 4.90–4.76 (m, 2H, POCH),
3.59–3.57 (m, 1H, CH2), 2.98–2.95 (m, 1H, CH2), 2.81–2.78 (m,
1H, CH2), 3.50–3.47 (m, 1H, CH2), 1.38–1.49 (m, 12H, (CH3)4). δC
(CDCl3) 170.8, 169.7 (C=O), 162.7 (d, JC,F 247.70, CF), 132.1, 116.4,
2
2
116.2 (ArCtert.), 75.4 (d, JC,P 7.12, POC), 73.3 (d, JC,P 7.63, POC),
47.9 (d, 1JC,P 149.9, PC), 36.5 (CH2), 31.3 (CH2), 24.9 (d, 3JC,P 1.53,
CH3), 24.3 (d, 3JC,P 3.56, CH3), 24.1 (d, 3JC,P 5.09, CH3), 23.7 (d, 3JC,P
6.61, CH3).
1-{[1-Benzyloxy-3-(diethoxyphosphoryl)-2,5-dioxopyrrolidin-
3-yl]methyl}piperidinum Chloride 6
Piperidine (1.02 g, 12 mmol) was added dropwise to a stirred solution of
2a (0.68 g, 2 mmol) in glacial acetic acid (4.6 mL), the mixture was
cooled to 30◦C and 35% formaldehyde (0.5 g, 16 mmol) was added.
The solution was stirred for 1h and then poured onto 12 g crushed ice.
The resulting mixture was made alkaline by slow addition of 30% NaOH
(5 mL) and then extracted with Et2O (3 × 10 mL).The solvent was evap-
orated and 1 M HCl (3 mL) was used to lower the pH to 2. This acidic
mixture was washed with EtOAc (2 × 5 mL). 30% NaOH (2 mL) was
used to raise the pH of the aqueous solution to 9. The crude base was
Diisopropyl (3-Benzyl-1-hydroxy-2,5-dioxopyrrolidin-
3-yl)phosphonate 4c
White solid (85%), mp 180.2◦C. (Found: C 54.90, H 6.55, N 3.82%.
C17H24NO6P requires C 55.28, H 6.55, N 3.79%.) νmax (KBr)/cm−1
1785, 1724 (C=O), 1243 (P=O), 1001 (POC). δH (CDCl3) 9.69 (s, 1H,
OH), 7.28–7.08 (m, 5H, ArH), 4.91–4.76 (m, 2H, POCH), 3.85–3.82
(m, 1H, CH2), 2.96–2.91 (m, 1H, CH2), 2.82–2.79 (m, 1H, CH2), 2.54–
2.51 (m, 1H, CH2), 1.50–1.36 (m, 12H, (CH3)4). δC (CDCl3) 170.9,

Synthesis of Derivatives of the Antibiotic SF-2312
287
extracted with EtOAc (3 × 5 mL). Dry HCl gas was passed through this
solution which was then cooled for 24 h at 4◦C, affording crystalline
6 (0.28 g, 21%). (Found: C 53.00 H 6.84 N 5.92%. C21H32ClN2O6P
requires C 53.11, H 6.79, N 5.90%.) νmax (KBr)/cm−1 1793, 1720 (C=
O), 1245 (P=O), 1010 (POC). δH ([D6]DMSO) 10.49 (s, 1H, NH), 7.50–
7.41 (m, 5H, ArH), 5.08 (s, 2H, CH2Ph), 4.16–4.12 (m, 4H, POCH2),
3.60–1.63 (m, 14H, CH2), 1.29–1.23 (m, 6H, CH3). δC ([D6]DMSO)
170.0, 168.6 (C=O), 134.9 (ArCquart.), 129.9, 129.5, 128.8 (ArCtert.),
78.7 (CH2Ph), 55.9 (d, 2JC,P 4.07, POC), 48.1 (CH2), 35.2 (CH2), 28.1
(CH2), 22.4 (CH2), 21.9 (CH2), 16.5 (q, 3JC,P 5.59, CH3).
3H, CH2), 2.40–2.33 (m, 1H, CH2). δC (D2O) 174.1, 174.0 (C=O),
133.4 (ArCquart.), 131.4, 130.3, 129.2 (ArCtert.), 121.4 (CH2), 79.5
(CH2PH), 57.9 (CH2OH), 47.7 (d, 1JC,P 125.12, PC), 41.6 (CH2NH3),
35.7 (CH2CH), 32.7 (CH2).
2-Hydroxyethanaminium Hydrogen[1-benzyloxy-
3-(4-methoxybenzyl)-2,5-dioxopyrrolidin-3-yl]phosphonate 8e
White solid (66%), mp 205◦C. (Found: C 53.27, H 5.91, N 5.77%.
C21H27N2O8P·1/2H2O requires C 53.04, H 5.93, N 5.89%.) νmax
(KBr)/cm−1 1784, 1712 (C=O). δH (D2O) 7.52–7.11 (m, 9H, ArH),
5.01–4.79 (m, 2H, CH2Ph), 3.91 (s, 3H, OCH3), 3.93–3.90 (m, 2H,
CH2NH3), 3.72–3.68 (m, 1H, CH2), 3.23 (t, J 5.30, 2H, CH2OH),
3.07–2.98 (m, 2H, CH2), 2.84–2.76 (m, 1H, CH2). δC (D2O) 174.5,
173.7 (C=O), 158.7, 133.5 (ArCquart.), 132.1, 130.6, 130.1, 129.0, 114.8
(ArCtert.), 79.7 (CH2Ph), 57.9 (CH2OH), 55.8 (OCH3), 41.6 (CH2NH3),
36.0 (CH2), 32.3 (CH2).
General Procedure for the Preparation of Ethanolamine
Monosalt Derivatives 8a–8j
To a solution of compounds 3 (3 mmol) in dry CH2Cl2 (5 mL) was
added trimethylsilyl bromide (0.92 g, 6 mmol) and the reaction mixture
was stirred at room temperature for 24 h. The solvent was evaporated
and the remaining oil was dissolved in MeOH (3 mL), treated with
water (0.1 mL), and stirred for 10 min.The solvents were removed under
reduced pressure and the residue dried in vacuo for 12 h. The resulting
phosphonic acids 7 were dissolved in dryTHF (5 mL), and ethanolamine
(0.17 g, 2.7 mmol) dissolved in 2 mL dry THF was added dropwise. The
solution was stirred for 1 h at RT and then kept at −18◦C for 2 days.
The solids formed were filtered and recrystallized from MeOH/Et2O to
give 8a–8e as white solids.
General Procedure for the Preparation of Compounds 9a–9e
Compounds 8a–8e (5 mmol) were dissolved in MeOH (100 mL), Pd-C
10% (300 mg) was added and the resulting mixture was hydrogenated
for 90 min.The suspension was filtered through an SPE tube RP-18.The
solvent was evaporated and the residue crystallized from MeOH/Et2O
to give 9a–9e.
2-Hydroxyethanaminium Hydrogen(3-benzyl-1-hydroxy-
2,5-dioxopyrrolidin-3-yl)phosphonate 9a
2-Hydroxyethanaminium Hydrogen(3-benzyl-1-benzyloxy-
2,5-dioxopyrrolidin-3-yl)phosphonate 8a
White solid (96%), mp 232◦C. (Found: C 44.83, H 5.36, N 7.92%.
C13H19N2O7P requires C 45.09, H 5.53, N 8.09%.) νmax (KBr)/cm−1
1780, 1697 (C=O). δH (D2O) 7.38–7.21 (m, 5H, ArH), 3.82 (t, J 5.92,
2H, CH2NH3), 3.67–3.62 (m, 1H, CH2), 3.14 (t, J 6.30, 2H, CH2OH),
3.05–2.97 (m, 2H, CH2), 2.96–2.75 (m, 1H, CH2). δC (D2O) 176.1,
174.3 (C=O), 135.5 (ArCquart.), 130.0, 129.2, 127.9 (ArCtert.), 57.9
White solid (57%), mp 175◦C. (Found: C 54.51, H 6.30, N 5.79%.
C20H25N2O7P requires C 55.05, H 5.77, N 6.42%.) νmax (KBr)/cm−1
1784, 1710 (C=O). δH (D2O) 7.27–6.95 (m, 10H, ArH), 4.74–4.55 (m,
2H, CH2Ph), 3.66 (t, J 6.49, 2H, CH2NH3), 3.53 (CH2), 2.98 (t, J 6.48,
2H, CH2OH), 2.86–2.76 (m, 2H, CH2), 2.60 (q, 1H, CH2). δC (D2O)
175.2, 173.6 (C=O), 135.7, 133.4 (ArCquart.), 130.7, 129.4, 129.1, 128.1
(ArCtert.), 79.7 (CH2Ph), 57.9 (CH2OH), 41.6 (CH2NH3), 48.2 (d, 1JC,P
142.92, PC), 36.9 (CH2), 32.4 (CH2).
1
(CH2OH), 49.0 (d, JC,P 126.65, PC), 41.6 (CH2NH3), 37.2 (CH2),
32.3 (CH2).
2-Hydroxyethanaminium Hydrogen[3-(4-fluorobenzyl)-
1-hydroxy-2,5-dioxopyrrolidin-3-yl]phosphonate 9b
2-Hydroxyethanaminium Hydrogen[1-benzyloxy-3-(4-fluorobenzyl)-
2,5-dioxopyrrolidin-3-yl]phosphonate 8b
White solid (90%), mp 160◦C. (Found: C 41.91, H 5.04, N 7.39%.
C13H18FN2O7P·1/2H2O requires C 41.81, H 5.13, N 7.51%.) νmax
(KBr)/cm−1 1782, 1697 (C=O). δH (D2O) 7.09–7.06 (m, 4H, ArH),
3.82 (t, J 7.75, 2H, CH2NH3), 3.64–3.59 (m, 1H, CH2), 3.14 (t, J 7.74,
2H, CH2OH), 3.06–2.90 (m, 2H, CH2), 2.74–2.67 (m, 1H, CH2). δC
(D2O) 176.0, 174.2 (C=O), 162.4 (d, JC,F 243.13, CF), 131.8, 115.7
(ArCtert.), 57.9 (CH2OH), 48.9 (d, 1JC,P 126.65, PC), 41.6 (CH2NH3),
36.4 (CH2), 32.2 (CH2).
White solid (68%), mp 172◦C. (Found: C 52.52, H 6.01, N 5.29%.
C20H24FN2O7P requires C 52.87, H 5.32, N 6.17%.) νmax (KBr)/cm−1
1786, 1712 (C=O). δH (D2O) 7.39–7.18 (m, 9H, ArH), 4.94–4.70 (m,
2H, CH2Ph), 3.83 (t, J 6.35, 2H, CH2NH3), 3.75–3.60 (m, 1H, CH2),
3.17(t, J6.38, 2H, CH2OH), 3.05–2.90(m, 2H, CH2), 2.70–2.60(m, 1H,
CH2). δC (D2O) 175.1, 173.5 (C=O), 162.5 (d, JC,F 243.13, CF), 133.4
(ArCquart.), 132.4, 130.6, 129.1, 116.2, 115.9 (ArCtert.), 79.7 (CH2Ph),
57.9 (CH2OH), 49.6 (d, 1JC,P 122.58, PC), 41.6 (CH2NH3), 35.9 (CH2),
32.3 (CH2).
2-Hydroxyethanaminium Hydrogen[1-hydroxy-3-(4-methylbenzyl)-
2,5-dioxopyrrolidin-3-yl]phosphonate 9c
2-Hydroxyethanaminium Hydrogen[1-benzyloxy-3-(4-methylbenzyl)-
2,5-dioxopyrrolidin-3-yl]phosphonate 8c
White solid (90%), mp 214◦C. (Found: C 45.83, H 5.87, N 7.60%.
C14H21N2O7P·1/2H2O requires C 45.51, H 6.01, N 7.59%.) νmax
(KBr)/cm−1 1780, 1701 (C=O). δH (D2O) 6.95–6.83 (m, 4H, ArH),
3.56 (m, J 6.52, 2H, CH2NH3), 3.36–3.32 (m, 1H, CH2), 2.88 (t, J 8.14,
2H, CH2OH), 2.78–2.67 (m, 2H, CH2), 2.48–2.41 (m, 1H, CH2), 2.03
(s, 3H, CH3). δC (D2O) 174.5, 174.3 (C=O), 138.1, 132.3 (ArCquart.),
130.2, 129.8 (ArCtert.), 57.9 (CH2OH), 48.0 (d, 1JC,P 127.05, PC), 41.6
(CH2NH3), 36.8 (CH2), 32.3 (CH2), 20.4 (CH3).
White solid (65%), mp 187◦C. (Found: C 55.68, H 6.05, N 6.19%.
C21H22N2O7P requires C 56.00, H 6.04, N 6.22%.) νmax (KBr)/cm−1
1786, 1712 (C=O). δH (D2O) 7.91–6.93 (m, 9H, ArH), 4.81–4.58 (m,
2H, CH2Ph), 3.72 (t, J 6.09, 2H, CH2NH3), 3.54–3.50 (m, 1H, CH2),
3.04 (t, J 6.47, 2H, CH2OH), 2.87–2.79 (m, 2H, CH2), 2.65–2.58 (m,
1H, CH2), 2.21 (s, 3H, CH3). δC (D2O) 173.7, 173.6 (C=O), 138.3,
130.7 (ArCquart.), 130.6, 130.1, 130.0, 129.1 (ArCtert.), 79.7 (CH2Ph),
57.9 (CH2OH), 49.6 (d, 1JC,P 123.60, PC), 41.6 (CH2NH3), 36.4 (CH2),
32.3 (CH2), 20.5 (CH3).
2-Hydroxyethanaminium Hydrogen(1-hydroxy-3-propyl-
2,5-dioxopyrrolidin-3-yl)phosphonate 9d
White solid (92%), mp 168◦C. (Found: C 35.94, H 6.45, N 9.28%.
C9H19N2O7P requires C 36.25, H 9.39, N 6.42%.) νmax (KBr)/cm−1
1780, 1701 (C=O). δH (D2O) 3.82 (t, J 5.06, 2H, CH2NH3), 3.14 (t, J
5.29, 2H, CH2OH), 3.07–2.81 (m, 2H, CH2), 2.15–2.05 (m, 1H, CH2),
1.83–1.74 (m, 1H, CH2), 1.41–1.33 (m, 1H, CH2), 1.19–1.06 (m, 1H,
CH2), 0.92 (t, J 7.40, 3H, CH3). δC (D2O) 176.9, 175.8 (C=O), 57.9
2-Hydroxyethanaminium Hydrogen(3-allyl-1-benzyloxy-2,5-
dioxopyrrolidin-3-yl)phosphonate 8d
White solid (64%), mp 169◦C. (Found: C 49.73, H 6.13, N 7.15%.
C16H23N2O7P requires C 49.74, H 6.00, N 7.25%.) νmax (KBr)/cm−1
1786, 1706 (C=O). δH (D2O) 7.47–7.45 (m, 5H, ArH), 5.38–5.28 (m,
1H, CHCH2), 5.17–5.13 (m, 2H, CHCH2), 5.10 (s, 2H, CH2Ph), 3.78
(t, J 5.12, 2H, CH2NH3), 3.10 (t, J 5.12, 2H, CH2OH), 2.92–2.67 (m,
1
2
(CH2OH), 48.0 (d, JC,P 127.16, PC), 41.6 (CH2NH3), 33.8 (d, JC,P
2.55, CCH2), 33.3 (CH2), 17.4 (d, 3JC,P 10.69, CH2CH3), 13.8 (CH3).

288
W. Owotoki, D. Geffken, and T. Kurz
2-Hydroxyethanaminium Hydrogen[1-hydroxy-
3-(4-methoxybenzyl)-2,5-dioxopyrrolidin-3-yl]phosphonate 9e
[5] E. Eguchi, M. Okuhara, M. Kohsaka, H. Aoki, H. Imanaka,
J. Antibiot. 1980, 33, 18.
[6] H. Jomaa, J. Wiesner, S. Sanderbrand, B. Altincicek,
C. Weidemeyer, M. Hintz, I. Türbachova, M. Eberl, J. Zeidler,
K. H. Lichtenahler, D. Soldati, E. Beck, Science 1999, 285, 1573.
doi:10.1126/SCIENCE.285.5433.1573
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White solid (96%), mp 214◦C. (Found: C 44.49, H 5.67, N 7.37%.
C14H21N2O8P requires C 44.69, H 5.62, N 7.44%.) νmax (KBr)/cm−1
1780, 1716 (C=O). δH (D2O) 7.17–6.95 (m, 4H, ArH), 3.84–3.82 (m,
2H, CH2NH3), 3.81 (s, 3H, OCH3), 3.61–3.56 (m, 1H, CH2), 3.15 (t, J
5.16, 2H, CH2OH), 3.05–2.92 (m, 2H, CH2), 2.74–2.68 (m, 1H, CH2).
δC (D2O) 176.2, 174.4 (C=O), 158.5, 127.9 (ArCquart.), 132.5, 114.6
(ArCtert.), 49.1 (d, 1JC,P 124.62, PC), 57.9 (CH2OH), 55.7 (OCH3), 41.6
(CH2NH3), 36.5 (CH2), 32.3 (CH2).
Acknowledgements
Financial support from the Grant of HmbNFG, Hamburg,
Germany, is gratefully acknowledged.
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44, 437.
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OrganicChemistry, 2ndedn 1999, Ch. 8, pp. 542–544(Blackwell:
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