Synthesis of model compounds for potential contrast agents containing phosphonate and peptide moieties

Article abstract of DOI:10.1039/a909086j

The synthesis of dimethyl 2-acetoxy-2-(2,4-diiodo-5-aminophenyl)ethylphosphonate and dimethyl 2-acetoxy-2-(2,4,6-triiodo-3,5-diaminophenyl)ethylphosphonate is described. Several amido and peptidic derivatives of these two compounds were prepared. These products are composed of a combination of structural/functional moieties which pave the way for their potential application as non-ionic selective X-ray contrast agents. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a909086j

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Synthesis of model compounds for potential contrast agents
containing phosphonate and peptide moieties
Hutti Shalem,a Shimon Shatzmiller*b and Ben-Ami Feita
1
a The Raymond and Beverly Sackler Faculty of Exact Sciences, School of Chemistry,
Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel
b The College of Jeudea and Samaria, Ariel 44837, Israel
Received (in Cambridge, UK) 16th November 1999, Accepted 19th April 2000
Published on the Web 7th July 2000
The synthesis of dimethyl 2-acetoxy-2-(2,4-diiodo-5-aminophenyl)ethylphosphonate and dimethyl 2-acetoxy-2-
(2,4,6-triiodo-3,5-diaminophenyl)ethylphosphonate is described. Several amido and peptidic derivatives of these
two compounds were prepared. These products are composed of a combination of structural/functional moieties
which pave the way for their potential application as non-ionic selective X-ray contrast agents.
X-Ray contrast agents for medical diagnosis available today are
hydrophilic, water-soluble derivatives of iodinated benzene
containing at least three iodine atoms, such as Iopamidol1 and
Iohexol.2 An ideal contrast agent should be completely bio-
logically inert, namely, stable, pharmacologically inactive and
efficiently and innocuously excretable. Generally, the clarity of
use of non-ionic contrast agents (e.g. Iohexol) has increased at
the expense of the ionic ones (e.g. sodium metrizoate). This is
due to the reduced osmolality, reduced toxicity and improved
saftey of the non-ionic contrast agents.2b,7
It was the purpose of the present research to design a novel
class of X-ray contrast agents (in potential), which both phos-
phonic acid and peptidic structural moieties are part of, and to
develop a synthetic approach for preparing model compounds
of this class.
Results and discussion
We report herein on a synthetic route to iodinated compounds
containing moieties of 2-(aminophenyl or amidophenyl)-2-
acetoxyethyl phosphonate, and on 2-acetoxy-2-(2,4,6-triiodo-
3,5-diaminophenyl)ethylphosphonate 12, as well as on some of
their amido and peptidic derivatives. These compounds might
pave the way, as model compounds, for developing selective
and efficient non-ionic contrast agents. The synthesis of the
2,4-diiodo-5-aminophenyl derivative 6 is outlined in Scheme 1.
3-Nitrobenzaldehyde 1 was used as a starting material for the
synthesis of the iodinated aromatic phosphonates. The first step
consisted of an addition reaction of the lithium salt of dimethyl
methylphosphonate 2 to the aldehydic function of 1. This
resulted in a racemic mixture of the hydroxynitrophosphonate
(rac-3) in a 97% yield.8
Acetylation of the hydroxy group of 3 to an acetate group
in 4 was carried out by reacting it with acetic anhydride in
pyridine as a solvent. Compound 4 was obtained in a quanti-
tative yield. The nitro compound 4 was reduced to the amino
compound 5, which provides the activation of the benzene ring
needed for introduction of the iodine atoms. The reduction,
which was carried out by catalytic hydrogenation, was quanti-
tative. Iodination of the aminophosphonate 5 was accom-
plished in an acetic acid solution with iodine monochloride9 to
give the diiodinated compound 6 in 81% yield. The product was
water-insoluble, and it could therefore be easily isolated and
purified. Attempts to form the triiodinated compound failed.
On carrying out the iodination of 5 in the presence of water, the
iodinated aminohydroxyphosphonate 7 was obtained in a yield
of 80%.
a contrast-enhanced diagnostic examination depends upon the
ability of the contrast agent to reach the targeted tissues and/or
organs, and on the amount of the X-ray energy absorbed in the
targeted region. In the case of ionic contrast agents, encapsulat-
ing water-soluble contrast media (CM), into liposomes3 could
be an alternative way towards a truly inert particular CM which
would not be rapidly filtered from the blood pool. Moreover, a
phospholipid-based compound covalently linked to an X-ray
contrast-giving moiety in the form of liposomes, which is used
i.v. for X-ray examination of the reticuloendothelial system
(especially the liver), has been recently reported.4 Thus, it might
be possible, based on a liposome system and on phospholipids
covalently linked to an X-ray contrast agent, that moieties of
phosphonic acids or esters thereof that are part of iodinated
aromatic compounds could enhance the ability of the contrast
agent to reach targeted tissues.5 In addition, incorporation of
such compounds (iodinated aromatic phosphonates) into short
peptides might enable the development of new potential con-
trast agents containing both phosphonic and peptidic moieties.
The peptidic moiety could affect the selective affinity of such
molecules towards specific tissues.6 During the last decade, the
The 2,4,6-triiodo-3,5-diaminophenyl derivative 12 was simi-
larly prepared using 3,5-dinitrobenzaldehyde10 8 as the starting
material (Scheme 2). The first step consisted of an addition
reaction of the lithium salt of dimethyl methylphosphonate 2 to
the aldehydic function of 8. This resulted in a racemic mixture
of the hydroxydinitrophosphonate (rac-9) in 50–60% yield.
DOI: 10.1039/a909086j
J. Chem. Soc., Perkin Trans. 1, 2000, 2831–2837
This journal is © The Royal Society of Chemistry 2000
2831

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formed in this iodination reaction mixture, which were isolated
by chromatography in 8% and 2% yields, respectively.
Each of the two compounds 6 and 12 was converted into
several amido derivates, thus introducing into these molecules
structural/functional features which could increase the poten-
tial activity of these derived products, as both selective and
effective contrast agents.
Several bis compounds, having the general structure 15 (15a–
15d) were prepared by reacting the 5-aminophenyl derivative 6
with each of several aliphatic diacyl chlorides, using pyridine as
a solvent [eqn. (1) and Table 1].
(1)
Table 1
n of X = (–CH2–)n
Yield of 15 (%)
a
b
c
0
2
4
6
78
46
89
80
d
It is noteworthy that each of the compounds 15a–15d, con-
tains two phosphonic acid ester groups, two (acetyl protected)
alcoholic functions and four iodine atoms. Basic hydrolysis11 of
the acetate groups in compounds 15a, 15b and 15d, using 1 M
NaOH solution in methanol, gave the following dihydroxy bis
compounds of type 16 listed in Table 2.
Scheme 1
Compounds 16a–16c were obtained in quantitative yields.
The diiodinated phosphonate
6
was coupled with
N-protected amino acids or with N-protected dipeptides to
yield iodinated aromatic compounds of type 17 containing a
peptidic moiety. The coupling reactions were carried out in
THF, by using isobutyl chloroformate12 (mixed anhydride
method) as a coupling reagent, in presence of N-methyl-
morpholine.
The synthesized target compounds of type 17 (Table 3) con-
tain an appropriate combination of functional moieties which
could significantly increase the efficiency and selectivity of
contrast agents, namely: diiodinated aromatic ring, a (pro-
tected) alcoholic function, a phosphonic acid ester moiety and
a peptidic moiety.
The diiodinated phosphonate 13 and the triiodinated phos-
phonate 12 were coupled with N-protected amino acid (t-Boc-
alanine or N-Cbz-glycine) to yield the corresponding iodinated
aromatic compounds of types 18, 19 and 20 containing a pep-
tidic moiety (Table 4). The coupling reactions were carried
Table 2
Scheme 2
Acetylation of the hydroxy group of 9 yielding the acetate
derivative 10 was carried out by reacting it with acetic
anhydride in pyridine as a solvent. The mixed ester 10 was
obtained in a quantitative yield. The dinitro compound 10 was
reduced by a catalytic hydrogenation to the derived diamino
phosphonate 11 which was obtained as a spongy solid in 95%
yield. Iodination of the diaminophosphonate 11 was accom-
plished in acetic acid using iodine monochloride9 as
the iodinating agent, to give the triiodo compound 12 in 30%
yield. Compounds 13 and 14 are two additional products
n of X = (–CH2–)n
a
b
c
0
2
6
2832
J. Chem. Soc., Perkin Trans. 1, 2000, 2831–2837

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Table 3
trometer at a frequency of 50.3 MHz. J values are given in Hz.
31P-NMR spectra were recorded with a Bruker ARX-500E
NMR spectrometer at a frequency of 202.46 MHz, by using
H3PO4 as an external standard. A double-focus 21-491B (Du-
Pont) spectrometer and VS Autospsec. M250 were used for
mass spectrometry. THF was purified by distillation over metal-
lic sodium. Pyridine was purified by distillation after standing
over KOH. Alumina (Merck, Aluminium oxide 90) and silica
(Merck, Silica gel 60H) were used for column chromatography.
Dimethyl 2-hydroxy-2-(3-nitrophenyl)ethylphosphonate 3
A precooled (Ϫ78 ЊC) solution of n-BuLi (1.6 M in n-hexane,
4.55 ml, 7.28 mmol) was added dropwise under dry nitrogen
during 15 min to a stirred solution of dimethyl methylphos-
phonate 2 (0.82 g, 6.62 mmol) in dry tetrahydrofuran (THF) at
Ϫ78 ЊC. A solution of the aldehyde 1 (1 g, 6.62 mmol) in 20 ml
of dry THF was introduced dropwise over 15 min, and the
reaction was allowed to continue for another 30 min at Ϫ78 ЊC,
and then another 30 min at room temperature. Water (20 ml)
was then added, and the mixture was extracted with three 20 ml
portions of diethyl ether, followed by extraction with two 20 ml
portions of CH2Cl2. The combined extracts were dried with
anhydrous MgSO4, and the residue which was obtained after
removal of the solvent was crystallized from dichloromethane–
petroleum ether (9:1) to give 3.53 g (97%) of 3 as a yellow solid,
mp 82 ЊC (Found: C, 43.28; H, 5.47; N, 5.02; P, 11.01.
C10H14NO6P requires C, 43.65; H, 5.13; N, 5.05; P, 11.26%);
IR(KBr), ν/cmϪ1 3338, 1532, 1244, 1038; δH 2.12–2.24 (2 H, m),
3.75 (3 H, d, J 10), 3.81 (3 H, d, J 10), 4.27 (1 H, br s), 5.14–5.29
(1 H, m), 7.53 (1 H, t, J 8), 7.75 (1 H, d, J 8), 8.14 (1 H, d, J 8),
8.25 (1 H, s); δC 35.12 (dt, JC-P 137.31), 52.42–52.89 (2q), 67.76
(dd, JC-P 4.07), 120.72 (d), 122.62 (d), 129.44 (d), 131.58 (d),
146.08 (d, JC-P 17.10), 148.51 (s); δP 31.62; m/z (%) 257 (10)
[Mϩ Ϫ 18], 152 (17), 124 (100), 109 (10).
Yield of
17 (%)
X
a
b
c
d
e
f
CH(Me)NHCO2CMe3
CH2NHCO2CH2Ph
CH(Me)NHCOCH(Me)NHCO2CMe3
CH2NHCOCH2NHCO2CH2Ph
CH2NHCO–CH(CH2CHMe2)NHCO2CH2Ph
CH(Me)NHCOCH2NHCO2CH2Ph
CH(CHMe2)NHCOCH(Me)NHCO2CH2Ph
30
60
30
28
20
17
50
g
Table 4
X
Y
Z
Dimethyl 2-acetoxy-2-(3-nitrophenyl)ethylphosphonate 4
18 NHCOCH2NHCO2CH2Ph
19 NH2
NHCOCH2NHCO2CH2Ph
NHCOCH2NHCO2CH2Ph
20 NHCOCH(Me)NHCO2CMe3 NHCOCH(Me)NHCO2CMe3
H
I
I
Acetic anhydride (0.68 ml, 7.27 mmol) was added to a stirred
solution of compound 3 (1 g, 3.63 mmol) in dry pyridine. The
reaction mixture was stirred overnight at room temperature.
The solvent was evaporated under reduced pressure. The resi-
due was dissolved in chloroform, washed twice with a cold solu-
tion of 2 M HCl, dried with anhydrous MgSO4, filtered and the
solvent was evaporated under reduced pressure to give 2.3 g
(quantitative yield) of 4 as a yellow oil (Found: C, 45.81; H,
5.18; N, 4.28. C12H16NO7P requires C, 45.43; H, 5.08; N, 4.42; P,
9.76%); IR(neat), ν/cmϪ1 1750, 1548, 1222, 1037; δH 2.11 (3 H, s),
2.18–2.62 (2 H, m), 3.66 (3 H, d, J 10), 3.69 (3 H, d, J 10), 6.10
(1 H, m), 7.55 (1 H, t, J 8), 7.72 (1 H, d, J 8), 8.18 (1 H, d, J 8),
8.24 (1 H, s); δC 20.83 (q), 32.42 (dt, JC-P 140.84), 52.25–52.46
(2q), 69.61 (d), 121.41 (d), 123.30 (d), 129.50 (d), 132.79 (d),
141.79 (d, JC-P 7.64), 148.47 (s), 168.90 (s); δP 27.53; m/z (%)
274 (50) [Mϩ Ϫ Ac], 258 (100) [Mϩ Ϫ OAc], 228 (6), 124 (5).
21 NHCOMe NHCOMe
H
out in THF, using isobutyl chloroformate12 (mixed anhydride
method) as a coupling reagent, in the presence of N-methyl-
morpholine.
The two aromatic amino groups in compound 13 were
acetylated to the corresponding acetamide derivative 21 in an
80% yield, by reaction with acetic anhydride in pyridine as a
solvent. It should be noted that amides, as functional groups in
contrast agents, proved to form effective linkages due to their
stability and high capacity to form transient bonds with hydro-
gens of the aqueous milieu.13 Compounds 18–20, which
contain a polyiodinated aromatic ring (contrast element), a
(protected) alcoholic function, a phosphonic acid ester moiety
and a peptidic residue might also be model compounds for effi-
cient contrast agents. The peptidic moiety could affect the
selective affinity of these potential contrast agents towards
specific tissues.6 The phosphonic ester, being part of the iodin-
ated aromatic compounds, could enhance the ability of the
contrast agent to reach targeted tissues.5
Dimethyl 2-acetoxy-2-(3-aminophenyl)ethylphosphonate 5
A catalytic amount of Pd/C (10% Pd) was added to a medium-
pressure hydrogenation flask which contained a solution of 4
(1.5 g, 4.73 mmol) in ethanol. The hydrogenation was carried
out at a pressure of 5 atm for 4 h. The solution was filtered and
dried with anhydrous MgSO4. The solvent was removed under
reduced pressure to give 1.34 g (99%) of 5 as a yellow oil
(Found: C, 49.84; H, 6.01; N, 5.03. C12H18NO5P requires C,
50.18; H, 6.32; N, 4.88; P, 10.78%); IR(neat) ν/cmϪ1 3388, 1652,
1211, 1043; δH 2.06 (3 H, s), 2.15–2.58 (2 H, m), 3.64 (3 H, d,
J 10), 3.66 (3 H, d, J 10), 5.96 (1 H, m), 6.64 (1 H, d, J 8), 6.73
(1 H, s), 6.75 (1 H, d, J 8), 7.11 (1 H, t, J 8); δC 21.08 (q), 32.46
(dt, JC-P 139.83), 52.16–52.58 (2q), 70.37 (d), 114.17 (d), 116.02
(d), 117.41 (d), 129.63 (d), 141.00 (d, JC-P 11.06), 144.93 (s),
169.24 (s); δP 27.71; m/z (%) 287 (99) [Mϩ], 245 (25) [MHϩ Ϫ
Ac], 288 (15) [Mϩ Ϫ OAc], 124 (6).
Experimental
General
Melting points were determined with a Buchi SMP-20 melting
point apparatus. IR spectra were recorded with a Nicolet
FT-IR 205 spectrometer. 1H-NMR spectra were recorded with
a Bruker AC-200E NMR spectrometer at a frequency of 200
MHz in CDCl3 using TMS as internal standard. 13C-NMR
spectra were recorded with a Bruker AC-200E NMR spec-
J. Chem. Soc., Perkin Trans. 1, 2000, 2831–2837
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Dimethyl 2-acetoxy-2-(2,4-diiodo-5-aminophenyl)ethyl-
phosphonate 6
JC-P 13.53); δP 30.44; m/z (%) 303 (12) [Mϩ Ϫ 17], 302 (10)
[Mϩ Ϫ 18], 272 (30) [Mϩ Ϫ OH Ϫ OMe], 124 (100).
A solution of iodine monochloride (1.41 g, 8.71 mmol) in 5 ml
of glacial acetic acid was added dropwise to a stirred solution
of 5 (1 g, 3.48 mmol) in 10 ml of glacial acetic acid, over a
period of 1.5 h. The reaction mixture was stirred at room tem-
perature for an additional 1–1.5 h. It was then heated to 80 ЊC,
kept at that temperature for 40 min and then allowed to cool
to room temperature. The excess of iodine monochloride was
eliminated by addition of solid sodium bisulfite followed by
sodium bicarbonate to pH 7. The reaction mixture was
extracted with three 20 ml portions of CH2Cl2. The combined
extracts were dried with anhydrous MgSO4, filtered, and the
solvent was evaporated under reduced pressure. The residue
was purified by chromatography (silica gel 60H) using methyl-
ene chloride as the eluent. 3.37 g (60%) of 6 were obtained as a
yellow solid, mp 128–129 ЊC (Found: C, 27.00; H, 3.14; N, 2.44.
C12H16I2NO5P requires C, 26.74; H, 2.99; I, 47.08; N, 2.60;
P, 5.75%); IR(KBr): ν/cmϪ1 3448, 1750, 1625, 1238, 1035, 762;
δH 2.12 (3 H, s), 2.19–2.33 (2 H, m), 3.71 (3 H, d, J 11), 3.77
(3 H, d, J 12), 6.03 (1 H, m), 6.78 (1 H, s), 7.97 (1 H, s); δC 20.91
(q), 31.14 (dt, JC-P 139.33), 52.46–52.79 (2q), 73.20 (d), 80.99 (s),
84.48 (s), 112.25 (d), 143.35 (d, JC-P 14.08), 147.50 (s), 147.71
(d), 169.15 (s); δP 27.85; m/z (%) 539 (28) [Mϩ], 412 (100)
[Mϩ Ϫ I], 352 (41) [Mϩ Ϫ OAc Ϫ 1].
Dimethyl 2-acetoxy-2-(3,5-dinitrophenyl)ethylphosphonate 10
Acetic anhydride (1.17 ml, 12.5 mmol) was added to a stirred
solution of compound 9 (2 g, 6.25 mmol) in dry pyridine. The
reaction mixture was stirred overnight at room temperature.
The solvent was evaporated under reduced pressure. The resi-
due was dissolved in chloroform, washed twice with a cold
solution of 2 M HCl, dried with anhydrous MgSO4, filtered
and the solvent evaporated under reduced pressure to give 3.39 g
(quantitative yield) of 10 as a yellow oil (Found: C, 39.91; H,
4.21; N, 7.89. C12H15N2O9P requires C, 39.79; H, 4.17; N, 7.73;
P, 8.55%); IR(neat): ν/cmϪ1 1747, 1541, 1346, 1228, 1031, 813;
δH 2.09 (3 H, s), 2.20–2.58 (2 H, m), 3.62 (3 H, d, J 12), 3.67
(3 H, d, J 12), 6.11 (1 H, m), 8.51 (2 H, d, J 2), 8.87 (1 H, d, J 2);
δC 20.77 (q), 32.15 (dt, JC-P 141.34), 52.58 (2q), 69.24 (d),
118.60 (d), 126.93 (2d), 144.20 (d, JC-P 9.55), 148.62 (2s),
168.96 (s); δP 26.43; m/z (%) 363 (100) [MHϩ], 303 (65)
[Mϩ Ϫ OAc], 273 (45), 257 (15), 210 (10).
Dimethyl 2-acetoxy-2-(3,5-diaminophenyl)ethylphosphonate 11
An equivalent amount of Pd/C (10% Pd) was added to a
medium-pressure hydrogenation flask which contained a solu-
tion of 10 (1.5 g, 4.14 mmol) in ethanol. The hydrogenation was
carried out at a pressure of 5 atm for 24 h. The solution
was filtered and dried with anhydrous MgSO4. The solvent was
removed under reduced pressure to give 1.18 g (95%) of 11 as a
spongy solid (Found: C, 48.00; H, 6.26; N, 8.92. C12H19N2O5P
requires C, 47.68; H, 6.34; N, 9.27; P, 10.25%); δH 2.06 (3 H,
s), 2.10–2.53 (2 H, m), 3.44 (br s), 3.67 (3 H, d, J 12), 3.68 (3 H,
d, J 12), 5.86 (1 H, m), 5.90 (1 H, d, J 2), 6.05 (2 H, d, J 2);
δC 21.03 (q), 32.30 (dt, JC-P 140.33), 52.48 (2q), 70.37 (d), 101.83
(d), 103.94 (2d), 142.11 (d, JC-P 10.81), 147.62 (2s), 169.44 (s);
δP 31.73; m/z (%) 303 (25) [MHϩ], 302 (35) [Mϩ], 243 (100)
[Mϩ Ϫ OAc].
Dimethyl 2-hydroxy-2-(2,4-diiodo-5-aminophenyl)ethyl-
phosphonate 7
This compound was prepared from 5 (0.5 g, 1.74 mmol) and ICl
(0.7 g, 4.35 mmol) in analogy to the preparation of compound
6, in 5 ml of glacial acetic acid. Iodine monochloride was added
to the reaction mixture and stirring was continued for an addi-
tional 1–1.5 h. Water (5–10 ml) was added, the reaction mix-
ture was further stirred for 30 min, and was slowly heated to
80 ЊC. The crude residue isolated after workup was crystallized
from CH2Cl2–petroleum ether (9:1) to give 1.29 g (50%) of 7
as a yellow-brown solid, mp 148–149 ЊC (Found: C, 24.32; H,
3.00; N, 2.63. C10H14I2NO4P requires C, 24.17; H, 2.84; I,
51.07; N, 2.82; P, 6.23%). IR(KBr): ν/cmϪ1 3363, 3020, 1605,
1216, 1023, 757; δH 1.77–2.41 (2 H, m), 3.73 (3 H, d, J 10),
3.84 (3 H, d, J 10), 4.22 (2 H, br s), 5.03 (1 H, m), 7.07 (1 H,
s), 7.92 (1 H, s); δC 33.19 (dt, JC-P 135.30), 51.58–52.33 (2q),
70.65 (dd, JC-P 5.03), 79.44 (s), 82.78 (s), 112.75 (d), 146.01
(s), 147.79 (d, JC-P 16.04), 149.08 (d); δP 31.35; m/z (%) 497.8
(45) [MHϩ], 479.8 (100) [MHϩ Ϫ 18], 387.9 (12) [Mϩ Ϫ 109],
369.9 (50) [Mϩ Ϫ I].
Dimethyl 2-acetoxy-2-(2,4,6-triiodo-3,5-diaminophenyl)ethyl-
phosphonate 12
A solution of iodine monochloride (0.94 g, 5.79 mmol) in 10 ml
of glacial acetic acid was added dropwise to a stirred solution
of 11 (0.5 g, 1.65 mmol) in 10 ml of glacial acetic acid over a
period of 1 h. The reaction mixture was stirred at room tem-
perature for an additional 1–1.5 h. It was then heated to 80 ЊC,
kept at that temperature for 1 h and then allowed to cool to
room temperature. The excess of iodine monochloride was
eliminated by addition of a 10% solution of sodium bisulfite
followed by sodium bicarbonate to pH 7. The reaction mixture
was extracted with three 20 ml portions of CH2Cl2. The com-
bined extracts were dried with anhydrous MgSO4, filtered, and
the solvent was evaporated under reduced pressure. The residue
was purified by chromatography (alumina) using ethyl acetate
and 5% methanol in ethyl acetate as the eluents. 1.34 g (30%) of
12 were obtained (Found: C, 20.86; H, 2.03; I, 56.32; N, 4.53.
C12H16I3N2O5P requires C, 21.20; H, 2.37; I, 55.99; N, 4.12; P,
4.56%); IR(neat): ν/cmϪ1 3471–3374, 2956, 1743, 1610, 1438,
1241, 1034, 761; δH 2.08 (3 H, s), 2.23–2.47 (1 H, m), 2.78–2.98
(1 H, m), 3.73 (3 H, d, J 12), 3.75 (3 H, d, J 12), 4.51 (br s), 6.65
(1 H, m); δC 20.68 (q), 28.26 (dt, JC-P 141.34), 52.58 (2q), 68.05
(d), 128.31 (2s), 139.69 (s), 169.57 (s); δP 28.70; ESMS: m/z (%)
636 (35) [Mϩ Ϫ Ac], 620 (55) [Mϩ Ϫ OAc].
Dimethyl 2-hydroxy-2-(3,5-dinitrophenyl)ethylphosphonate 9
A precooled (Ϫ78 ЊC) solution of n-BuLi (1.6 M in n-hexane,
7.01 ml, 11.22 mmol) was added dropwise under dry nitrogen
for 15 min to a stirred solution of dimethyl methylphosphonate
2 (1.26 g, 10.20 mmol) in dry tetrahydrofuran (THF) at Ϫ78 ЊC.
A solution of the aldehyde 8 (2 g, 10.20 mmol) in 40 ml of dry
THF was introduced dropwise over 5 min, and the reaction was
allowed to continue for another 30 min at Ϫ78 ЊC, and then
another 30 min at room temperature. Water (40 ml) was then
added and the mixture was extracted with three 40 ml portions
of diethyl ether, followed by extraction with two 40 ml portions
of CH2Cl2. The combined extracts were dried with anhydrous
MgSO4 and the residue, obtained after removal of the solvent,
was crystallized from dichloromethane–petroleum ether (8:2)
to give 3.59 g (55%) of 9 as a white solid, mp 88–89 ЊC (Found:
C, 37.66; H, 4.09; N, 8.93. C10H13N2O8P requires C, 37.51; H,
4.09; N, 8.75; P, 9.67%); IR(KBr): ν/cmϪ1 3248, 1535, 1342,
1230, 1032, 856; δH 2.13–2.28 (2 H, m), 3.79 (3 H, d, J 12), 3.85
(3 H, d, J 12), 4.79 (br s, OH), 5.29 (1 H, m), 8.61 (2 H, d, J 2),
8.95 (1 H, d, J 2); δC 33.61 (dt, JC-P 136.81), 51.68–52.00 (2q),
66.46 (d), 117.26 (d), 126.50 (2d), 147.79 (2s), 149.70 (d,
Dimethyl 2-acetoxy-2-(2,6-diiodo-3,5-diaminophenyl)ethyl-
phosphonate 13. Compound 13 was obtained as a by-product
by iodination of 11, after purification of the crude reaction
product by chromatography, in a yield of 8% (0.21 g) (Found:
C, 25.67; H, 3.19; I, 46.12; N, 4.83. C12H17I2N2O5P requires C,
26.01; H, 3.09; I, 45.81; N, 5.06; P, 5.59%); IR(neat): ν/cmϪ1
3460–3320, 2946, 1741, 1620, 1418, 1240, 1033, 759; δH 2.13
2834
J. Chem. Soc., Perkin Trans. 1, 2000, 2831–2837

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(3 H, s), 2.31–2.48 (1 H, m), 3.74 (3 H, d, J 10), 3.76 (3 H, d,
J 10), 6.68 (1 H, m), 7.95 (1 H, s); δC 20.67 (q), 28.21 (dt, JC-P
140.33), 52.58 (2q), 68.05 (d), 107.41 (d), 111.55 (2s), 133.58 (s),
169.60 (s); δP 28.44; m/z (%) 553 (3) [Mϩ], 426 (2) [Mϩ Ϫ 127],
317 (90) [Mϩ Ϫ 127 Ϫ 109], 274 (29) [317 Ϫ43], 109 (40) [-PO3-
Me2], 43 (100) [-Ac].
perature for 2 h and then allowed to cool to room temperature.
The work up was performed analogously to that used for
preparation of 15a to give 0.292 g (89%) of 15c as a yellow oil
(Found: C, 29.98; H, 3.01; I, 43.10; N, 2.09. C30H38I4N2O12P2
requires C, 30.33; H, 3.22; I, 42.72; N, 2.36; P, 5.21%); IR(neat):
ν/cmϪ1 3305, 2962, 1744, 1690, 1554, 1371, 1260, 1027, 800;
δH 1.85 (4 H, t, J 6), 2.19 (6 H, s), 2.19–2.34 (4 H, m), 2.49 (4 H,
t, J 6), 3.75 (6 H, d, J 12), 3.77 (6 H, d, J 12), 6.08 (2 H, m), 7.50
(2 H, s), 8.16 (2 H, s), 8.33 (2 H, s); δC 20.93 (2q), 24.71 (2t),
31.31 (2dt, JC-P 138.82), 37.43 (2t), 52.55 (4q), 73.45 (2dd,
JC-P 5.03), 89.72 (2s), 90.31 (2s), 119.37 (2d), 139.09 (2s),
144.16 (2s), 147.67 (2d), 169.01 (2s), 170.41 (2s); δP 27.72; m/z
(%) 1188.8 (90) [Mϩ], 1128.6 (10) [Mϩ Ϫ OAc], 1068.7 (100)
[MHϩ Ϫ 2OAc], 942.8 (40) [Mϩ Ϫ 2(CH2PO3Me2)].
Dimethyl 2-hydroxy-2-(2,4,6-triiodo-3,5-diaminophenyl)ethyl-
phosphonate 14. Compound 14 was obtained as a by-product
by iodination of 11, after purification of the crude reaction
product by chromatography, in a yield of 2% (0.084 g) (Found:
C, 18.76; H, 2.45; N, 4.13; I, 60.02. C10H14I3N2O4P requires C,
18.83; H, 2.21; I, 59.68; N, 4.39; P, 4.86%); δH 2.32–2.51 (1 H,
m), 2.66–2.86 (1 H, m), 3.68 (3 H, d, J 12), 3.72 (3 H, d, J 12),
5.83 (1 H, m); δC 31.46 (dt, JC-P 148.84), 53.39 (2q), 67.53 (d),
108.32 (s), 136.89 (s), 142.11 (s); δP 28.45; m/z (%) 639.25 (14)
[MHϩ], 603.36 (29) [Mϩ Ϫ 18 Ϫ NH2], 577.37 (70) [MHϩ Ϫ
2(OMe)], 549.34 (100).
N,NЈ-Bis{2,4-diiodo-5-[1-acetoxy-2-(dimethoxyphosphoryl)-
ethyl]phenyl}octanediamide 15d
This compound was prepared analogously to 15a from 6 (0.15
g, 0.278 mmol) and suberoyl chloride (0.025 ml, 0.139 mmol) to
yield 0.405 g (80%) of 15d as an oil (Found: C, 31.89; H, 3.73;
I, 41.52; N, 2.17. C32H42I4N2O12P2 requires C, 31.60; H, 3.48; I,
41.74; N, 2.30; P, 5.09%); IR(neat): ν/cmϪ1 3300, 2953, 1744,
1681, 1498, 1371, 1235, 1034, 753; δH 1.47 (4 H, m), 1.78 (4 H,
m), 2.14 (6 H, s), 2.25–2.48 (8 H, m), 3.76 (6 H, d, J 12), 3.77
(6 H, d, J 12), 6.09 (2 H, m), 7.48 (2 H, s), 8.19 (2 H, s), 8.35
(2 H, s); δC 20.89 (2q), 25.09 (2t), 28.75 (2t), 31.06 (2dt, JC-P
139.83), 37.71 (2t), 52.58 (4q), 73.59 (2d), 89.83 (2s), 90.14 (2s),
119.13 (2d), 139.01 (2s), 143.98 (2d, JC-P 14.08), 147.61 (2d),
169.39 (2s), 171.16 (2s); δP 27.75; m/z (%) 1216.6 (100) [MHϩ],
1098 (73) [Mϩ Ϫ 2OAc], 970 (25) [Mϩ Ϫ 2(CH2PO3Me2)].
N,NЈ-Bis{2,4-diiodo-5-[1-acetoxy-2-(dimethylphosphoryl)-
ethyl]phenyl}oxamide 15a
Oxalyl chloride (0.01 ml, 0.13 mmol) was added under nitrogen
to a stirred solution of 6 (0.15 g, 0.27 mmol) in dry pyridine (2
ml) at 0 ЊC. The reaction mixture was stirred for 1 h at that
temperature and then was heated to room temperature and fur-
ther stirred for 4 h. A cold aqueous solution of 10% HCl was
then added to the reaction mixture (to pH 7). The reaction
mixture was extracted with five 5 ml portions of CH2Cl2. The
combined organic extracts were washed with water, then with a
2% NaHCO3 solution, and again with water. The organic phase
was dried with anhydrous MgSO4 and filtered. The solvent was
removed from the filtrate under reduced pressure to give 0.35 g
(78%) of 15a as a yellow oil (Found: C, 27.82; H, 2.86; N, 2.31.
C26H30I4N2O12P2 requires C, 27.58; H, 2.67; I, 44.84; N, 2.47; P,
5.47%); IR(neat): ν/cmϪ1 3300, 2955, 1745, 1561, 1444, 1372,
1221, 1031, 755; δH 2.15 (6 H, s), 2.24–2.36 (4 H, m), 3.75 (6 H,
d, J 10), 3.76 (6 H, d, J 10), 6.07 (2 H, m), 8.24 (2 H, s), 8.43
(2 H, br s), 8.45 (2 H, s); δC 17.25 (2q), 30.11 (2dt, JC-P 139.83),
51.67 (4q), 72.58 (2d), 88.64 (2s), 91.18 (2s), 117.34 (2d), 136.59
(2s), 143.42 (2d, JC-P 13.07), 147.32 (2d), 156.12 (2s), 168.36
(2s); δP 28.10; m/z (%) 1132.5 (100) [MHϩ], 1072 (5) [Mϩ Ϫ
OAc], 1013 (72) [Mϩ Ϫ 2OAc].
N,NЈ-Bis{2,4-diiodo-5-[1-hydroxy-2-(dimethoxyphosphoryl)-
ethyl]phenyl}oxamide 16a
A solution of 1 M NaOH (0.795 ml, 0.795 mmol) was added to
a stirred solution of 15a (0.2 g, 0.176 mmol) in methanol (the
amount needed for dissolving 15a). The reaction mixture was
stirred at room temperature for 4 h and the methanol was then
evaporated under reduced pressure. The residue left behind was
acidified to pH 7 using aqueous 1 M HCl solution. The aqueous
reaction mixture was extracted with five 5 ml portions of
dichloromethane. The combined extracts were dried with
anhydrous MgSO4, filtered, and the solvent evaporated under
reduced pressure to give 0.185 g (quantitative yield) of 16a
(Found: C, 24.92; H, 2.83; I, 48.11; N, 2.93. C22H26I4N2O10P2
requires C, 25.21; H, 2.50; I, 48.44; N, 2.67; P, 5.91%); IR(neat):
ν/cmϪ1 3400, 2360, 1698, 1558, 1372, 1180, 1029; δH 1.98–2.37
(4 H, m), 3.74 (6 H, d, J 10), 3.78 (6 H, d, J 10), 5.15 (2 H, m),
8.25 (2 H, s), 8.32 (2 H, s); δC 34.38 (2dt, JC-P 137.82), 53.60 (4q),
73.13 (2d), 92.47 (2s), 93.82 (2s), 122.65 (2d), 140.28 (2s), 149.71
(2d), 150.04 (2d, JC-P 16.09), 162.98 (2s); δP 31.58; m/z (%) 1071
(25) [MNaϩ], 1048 (100) [Mϩ], 1012 (35) [Mϩ Ϫ 2H2O].
N,NЈ-Bis{2,4-diiodo-5-[1-acetoxy-2-(dimethoxyphosphoryl)-
ethyl]phenyl}succinamide 15b
Succinyl chloride (0.03 ml, 0.27 mmol) was added under nitro-
gen to a solution of 6 (0.3 g, 0.55 mmol) in dry pyridine. The
reaction mixture was stirred for 24 hours at room temperature.
The work-up was performed analogously to that used for the
preparation of 15a. The crude residue was purified by chrom-
atography (Alumina) using 2% methanol in ethyl acetate as
the eluent. 0.43 g (46%) of 15b were obtained as a yellow oil
(Found: C, 29.11; H, 3.13; I, 44.03; N, 2.21. C28H34I4N2O12P2
requires C, 28.99; H, 2.95; I, 43.75; N, 2.41; P, 5.34%); IR(neat):
ν/cmϪ1 3290, 2955, 1744, 1683, 1557, 1499, 1371, 1237, 1030,
757; δH 2.13 (6 H, s), 2.25–2.37 (4 H, m), 2.88 (4 H, s), 3.75 (6 H,
d, J 10), 3.76 (6 H, d, J 10), 6.08 (2 H, m), 7.74 (2 H, s), 8.20
(2 H, s), 8.33 (2 H, s); δC 20.99 (2q), 31.14 (2dt, JC-P 39.33), 32.36
(2t), 52.58 (2q), 52.68 (2q), 73.64 (2d), 89.71 (2s), 90.53 (2s),
119.33 (2d), 138.97 (2s), 144.02 (2d, JC-P 13.58), 147.86 (2d),
169.39 (2s), 169.93 (2s); δP 27.67; m/z (%): 1160.6 (100) [MHϩ],
1041 (60) [Mϩ Ϫ 2OAc], 914 (25) [Mϩ Ϫ 2(CH2PO3Me2)].
N,NЈ-Bis{2,4-diiodo-5-[1-hydroxy-2-(dimethoxyphosphoryl)-
ethyl]phenyl}succinamide 16b
This compound was prepared analogously to 16a from 15b (0.2
g, 0.172 mmol) and 1 M NaOH solution (0.775 ml, 0.775
mmol), to give 0.185 g (quantitative yield) of 16b (Found: C,
26.54; H, 3.00; N, 2.89. C24H30I4N2O10P2 requires C, 26.77; H,
2.81; I, 47.17; N, 2.60; P, 5.76%); δH 1.98–2.38 (4 H, m), 2.87
(4 H, s), 3.76 (6 H, d, J 10), 3.83 (6 H, d, J 10), 5.14 (2 H, “t”),
7.74 (2 H, s), 8.17 (2 H, s), 8.39 (2 H, s); δC 2.07–2.27 (4 H, m),
2.83 (4 H, s), 3.74 (6 H, d, J 12), 3.77 (6 H, d, J 12), 5.12 (2 H,
m), 7.75 (2 H, s), 8.29 (2 H, s); δP 31.36; m/z (%) 1076.7 (100)
[MHϩ], 1040.8 (12) [Mϩ Ϫ 2OH], 951 (32) [Mϩ Ϫ 124].
N,NЈ-Bis{2,4-diiodo-5-[1-acetoxy-2-(dimethoxyphosphoryl)-
ethyl]phenyl}hexanediamide 15c
N,NЈ-Bis{2,4-diiodo-5-[1-hydroxy-2-(dimethoxyphosphoryl)-
ethyl]phenyl}octanediamide 16c
Adipoyl chloride (0.013 ml, 0.092 mmol) was added under
nitrogen to a stirred solution of 6 (0.1 g, 0.185 mmol), in dry
pyridine. The reaction mixture was stirred for 1 h at room
temperature and then slowly heated to 50 ЊC, kept at room tem-
This compound was prepared analogously to 16a from 15d
(0.038 g, 0.031 mmol) and 1 M NaOH solution (0.140 ml, 0.140
J. Chem. Soc., Perkin Trans. 1, 2000, 2831–2837
2835

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mmol), to give 0.035 g (quantitative yield) of 16c (Found: C,
30.03; H, 3.01; I, 45.12; N, 2.33. C28H38I4N2O10P2 requires C,
29.70; H, 3.38; I, 44.84; N, 2.47; P, 5.47%); IR(neat): ν/cmϪ1
3540, 2963, 1733, 1448, 1370, 1220, 1033, 754; δH 1.46 (4 H, m),
1.77 (4 H, m), 2.01–2.46 (8 H, m), 3.78 (6 H, d, J 10), 3.83 (6 H,
d, J 10), 5.14 (2 H, m), 7.49 (2 H, d, J 10), 8.15 (2 H, d, J 3), 8.34
(2 H, d, J 8); δC 25.03 (2t), 28.64 (2t), 29.67 (2t), 35.86 (2dt, JC-P
147.37), 52.84 (4q), 71.85 (2d), 90.26 (2s), 90.53 (2s), 120.88
(2d), 139.13 (2s), 147.30 (2d ϩ 2s), 171.33 (2s); δP 31.71; m/z (%)
1155 (15) [MNaϩ], 1132 (100) [Mϩ].
C23H34I2N3O9P requires C, 35.36; H, 4.39; I, 32.48; N, 5.38; P,
3.96%); IR(neat): ν/cmϪ1 3350, 1702, 1501, 1370, 1240, 1031,
753; δH 1.38–1.50 (15 H, m), 2.14 (3 H, s), 2.24–2.36 (2 H, m),
3.76 (3 H, d, J 12), 3.77 (3 H, d, J 12), 4.24 (1 H, m), 4.63 (1 H,
m), 4.91 (1 H, br s), 6.10 (1 H, m), 7.01 (1 H, br s), 8.20 (1 H, s),
8.26 (1 H, s), 8.29 (1 H, br s); δC 17.27 (q), 17.57 (q), 20.93 (q),
28.26 (3q), 31.10 (dt, JC-P 139.83), 49.88 (2d), 52.63 (2q), 73.59
(d), 80.67 (s), 90.31 (s), 90.63 (s), 119.66 (d), 139.09 (s), 143.92
(d, JC-P 13.58), 147.94 (d), 155.82 (s), 169.41 (s), 170.28 (s),
173.12 (s); δP 27.63; m/z (%) 804 (10) [MNaϩ], 781 (23) [Mϩ], 681
(38) [Mϩ Ϫ CO2CMe3], 621 (97) [Mϩ Ϫ CO2CMe3 Ϫ OAc].
Dimethyl 2-acetoxy-2-{2,4-diiodo-5-[N-(tert-butyloxycarbonyl)-
alanylamino]phenyl}ethylphosphonate 17a
Dimethyl 2-acetoxy-2-{2,4-diiodo-5-[N-(benzyloxycarbonyl)-
glycylglycylamino]phenyl}ethylphosphonate 17d
Isobutyl chloroformate (0.072 ml, 0.555 mmol) was added
dropwise to a solution of t-Boc-alanine (1.05 g, 0.555 mmol)
and N-methylmorpholine (0.66 ml, 0.555 mmol) in dry THF (5
ml) at Ϫ20 ЊC (CO2/CCl4 bath) and the reaction mixture stirred
for 15 min. A solution of 6 (0.3 g, 0.555 mmol) in dry THF (3
ml) was then introduced dropwise over 15 min, and the reaction
mixture was further stirred for another 1 h at Ϫ20 ЊC, followed
by additional 15 min at room temperature. The reaction mix-
ture was filtered, and the solvent was evaporated under reduced
pressure. The residue was dissolved in 20 ml of CH2Cl2, washed
with 0.2 M HCl solution, then with 5% NaHCO3 solution and
then with brine. The organic phase was dried using anhydrous
MgSO4, filtered, and the solvent was evaporated under reduced
pressure. The residue was purified by chromatography (alu-
mina) using a 5% methanol solution in ethyl acetate as the
eluent, to give 0.236 g (30%) of 17a as an oil (Found: C, 33.93;
H, 4.42; N, 3.58. C20H29I2N2O8P requires C, 33.82; H, 4.12; I,
35.74; N, 3.94; P, 4.36%); IR(neat): ν/cmϪ1 3400, 1690, 1499,
1371, 1246, 1030; δH 1.47–1.50 (9 H ϩ 3 H, s ϩ d), 2.14 (3 H, s),
2.22–2.34 (2 H, m), 3.76 (3 H, d, J 12), 3.77 (3 H, d, J 12), 4.32
(1 H, br s), 4.92 (1 H, d, J 6), 6.07 (1 H, m), 8.18 (1 H, s), 8.39
(1 H, s), 8.42 (1 H, d, J 4); δH 17.88 (q), 20.95 (q), 28.54 (3q),
31.32 (dt, JC-P 139.83), 51.44 (d), 52.53–52.63 (2q), 73.55 (d),
80.81 (s), 89.38 (s), 90.30 (s), 118.92 (d), 139.17 (s), 144.27
(d, JC-P 15.69), 147.81 (d), 155.33 (s), 169.11 (s), 170.94 (s);
δC 27.68; m/z (%) 733 (10) [MNaϩ], 711 (100) [MHϩ], 654 (25)
[MHϩ Ϫ 57], 594 (21) [MHϩ Ϫ 57 Ϫ 59].
This compound was prepared analogously to 17c from N-Cbz-
glycylglycine (0.49 g, 1.85 mmol) and amine 6 (0.5 g, 0.92
mmol) to yield 0.4 g (28%) of 17d as an oil (Found: C, 35.15;
H, 3.31; I, 31.87; N, 5.08. C24H28I2N3O9P requires C, 36.62; H,
3.58; I, 32.24; N, 5.34; P, 3.93%); IR(neat): ν/cmϪ1 3350, 1700,
1505, 1237, 1036, 755; δH 2.11 (3 H, s), 2.21–2.37 (2 H, m), 3.73
(3 H, d, J 12), 3.74 (3 H, d, J 12), 3.98 (2 H, d, J 6), 4.07 (2 H, d,
J 6), 5.11 (2 H, s), 5.82 (1 H, br s), 6.07 (1 H, m), 7.33 (5 H, s),
7.38 (1 H, br s), 8.18–8.20 (3 H, s ϩ br s); δC 20.88 (q), 30.80 (dt,
JC-P 139.33), 44.26 (t), 44.58 (t), 52.75 (2q), 67.34 (t), 73.48 (d),
90.57 (s), 91.14 (s), 119.90 (d), 128.10 (2d), 128.31 (d), 128.53
(2d), 135.84 (s), 138.61 (s), 143.66 (d, JC-P 12.57), 147.92 (d),
158.74 (s), 167.27 (s), 169.42 (s), 170.34 (s); δP 27.69; m/z (%)
788 (100) [MHϩ], 728 (25) [Mϩ Ϫ OAc].
Dimethyl 2-acetoxy-2-{2,4-diiodo-5-[N-(benzyloxycarbonyl)-
leucylglycylamino]phenyl}ethylphosphonate 17e
This compound was prepared analogously to 17c from N-Cbz-
leucylglycine (0.59 g, 1.85 mmol) and amine 6 (0.5 g, 0.92
mmol) to yield 0.31 g (20%) of 17e as an oil (Found: C, 40.15;
H, 4.48; N, 5.20. C28H36I2N3O9P requires C, 39.88; H, 4.30; I,
30.09; N, 4.98; P, 3.67%); IR(neat): ν/cmϪ1 3300, 1698, 1502,
1237, 1036, 756; δH 0.96 (6 H, d, J 8), 1.57–1.73 (3 H, m), 2.11
(3 H, s), 2.24–2.36 (2 H, m), 3.73 (3 H, d, J 10), 3.74 (3 H, d,
J 10), 4.09 (2 H, d, J 6), 4.37 (1 H, “t”), 5.07 (2 H, s), 5.68 (1 H,
br s), 6.07 (1 H, m), 7.30 (5 H, s), 7.59 (1 H, br s), 8.17 (1 H, s),
8.24 (1 H, br s), 8.29 (s, 1 H); δC 20.84 (q), 21.75 (q), 23.00 (q),
24.66 (d), 30.91 (dt, JC-P 138.82), 41.34 (t), 44.44 (t), 52.73 (2q),
53.53 (d), 67.22 (t), 73.47 (d), 90.69 (s), 91.12 (s), 120.15 (d),
127.99 (2d), 128.23 (d), 128.50 (2d), 135.87 (s), 138.83 (s), 143.55
(d, JC-P 13.58), 147.94 (d), 156.36 (s), 164.48 (s), 169.37
(s), 173.66 (s); δP 27.69; m/z (%) 844 (100) [MHϩ], 784 (30)
[Mϩ Ϫ OAc].
Dimethyl 2-acetoxy-2-{2,4-diiodo-5-[N-(benzyloxycarbonyl)-
glycylamino]phenyl}ethylphosphonate 17b
This compound was prepared analogously to 17a from N-Cbz-
glycine (0.15 g, 0.74 mmol) and compound 6 (0.2 g, 0.37 mmol)
to yield 0.32 g (60%) of 17b as an oil (Found: C, 35.91; H, 3.81;
I, 35.10; N, 4.12. C22H25I2N2O8P requires C, 36.19; H, 3.45; I,
34.76; N, 3.84; P, 4.24%); IR(neat): ν/cmϪ1 3343, 1720, 1702,
1239, 1030; δH 2.12 (3 H, s), 2.20–2.32 (2 H, m), 3.74 (3 H, d,
J 12), 3.75 (3 H, d, J 12), 3.99 (2 H, d, J 6), 5.15 (2 H, s), 5.77
(1 H, t, J 6), 6.03 (1 H, m), 7.32 (5 H, s), 8.13 (1 H, s), 8.24 (1 H,
s), 8.32 (1 H, s); δC 20.85 (q), 31.09 (dt, JC-P 137.82), 45.89 (t),
52.53 (q), 52.62 (q), 67.45 (t), 73.42 (d), 89.77 (s), 90.57 (s),
119.09 (d), 128.58 (5d), 136.02 (s), 138.72 (s), 144.02 (d, JC-P
13.58), 147.71 (d), 156.63 (s), 167.64 (s), 169.03 (s); δP 27.84; m/z
(%) 735 (5) [MNaϩ], 731 (100) [MHϩ], 671 (10) [Mϩ Ϫ OAc].
Dimethyl 2-acetoxy-2-{2,4-diiodo-5-[N-(benzyloxycarbonyl)-
glycylalanylamino]phenyl}ethylphosphonate 17f
This compound was prepared analogously to 17c from N-Cbz-
glycylalanine (0.31 g, 1.11 mmol) and amine 6 (0.3 g, 0.55
mmol) to yield 0.15 g (17%) of 17f as an oil (Found: C, 37.85;
H, 3.98; N, 5.41. C25H30I2N3O9P requires C, 37.47; H, 3.77; I,
31.67; N, 5.24; P, 3.87%); IR(neat): ν/cmϪ1 3400, 2360, 1702,
1500, 1245, 1047, 753; δH 1.46 (3 H, d, J 6), 2.12 (3 H, s), 2.24–
2.36 (2 H, m), 3.73 (3 H, d, J 10), 3.75 (3 H, d, J 10), 3.96 (2 H,
d, J 6), 4.66 (1 H, q, J 6), 5.12 (2 H, s), 5.70 (1 H, br s), 6.08
(1 H, m), 7.04 (1 H, br s), 7.33 (5 H, s), 8.19 (1 H, s), 8.21 (1 H,
s), 8.29 (1 H, s); δC 17.32 (q), 20.96 (q), 31.04 (dt, JC-P 137.82),
44.66 (t), 49.84 (d), 52.50–52.76 (2q), 67.37 (t), 73.56 (d), 90.58
(s), 91.04 (s), 119.87 (d), 128.13 (2d), 128.35 (d), 128.57 (2d),
135.91 (s), 138.92 (s), 143.76 (d, JC-P 12.57), 147.94 (d), 156.70
(s), 169.43 (s), 169.61 (s), 170.18 (s); δP 27.63; m/z (%) 802 (100)
[MHϩ], 742 (30) [Mϩ Ϫ OAc].
Dimethyl 2-acetoxy-2-{2,4-diiodo-5-[N-(tert-butoxycarbonyl)-
alanylalanylamino]phenyl}ethylphosphonate 17c
This compound was prepared analogously to 17a from t-Boc-
alanylalanine (0.28 g, 1.11 mmol) and amine 6 (0.3 g, 0.55
mmol). After letting the reaction mixture warm to room
temperature, it was slowly heated to 50 ЊC and allowed to stay
at that temperature for 1 h. Work-up was carried out in analogy
to that applied for 17a. The residue obtained after work-up was
purified by chromatography (alumina) using a 10% solution of
methanol in ethyl acetate as the eluent to give 0.26 g (30%) of
17c as a yellow oil (Found: C, 35.16; H, 4.01; I, 32.09; N, 5.72.
Dimethyl 2-acetoxy-2-{2,4-diiodo-5-[N-(benzyloxycarbonyl)-
alanylvalylamino]phenyl}ethylphosphonate 17g
This compound was prepared analogously to 17c from N-Cbz-
2836
J. Chem. Soc., Perkin Trans. 1, 2000, 2831–2837

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alanylvaline (0.89 g, 2.78 mmol) and amine 6 (0.5 g, 0.92 mmol)
to yield 0.78 g (50%) of 17g as an oil (Found: C, 39.79; H, 4.55;
N, 4.81. C28H36I2N3O9P requires C, 39.88; H, 4.30; I, 30.09; N,
4.98; P, 3.67%); IR(neat): ν/cmϪ1 3290, 2952, 1702, 1500, 1236,
1030, 752; δH 0.92–1.02 (6 H, m), 1.39–1.45 (3 H, m), 2.12 (3 H,
s), 2.17–2.36 (2 H, m), 3.74 (3 H, d, J 10), 3.75 (3 H, d, J 10),
4.33–4.47 (2 H, m), 5.10 (2 H, d, J 6), 5.60–5.70 (1 H, m), 6.02–
6.14 (1 H, m), 7.14 (1 H, br d, J 6), 7.31 (5 H, s), 8.14–8.24 (3 H,
m); δC 17.68 (q), 18.72 (q), 19.36 (q), 20.89 (q), 30.23 (d), 30.99
(dt, JC-P 140.33), 50.50 (d), 52.42–52.69 (2q), 59.54 (d), 67.15 (t),
73.46 (d), 90.42 (s), 90.95 (s), 119.69 (d), 128.04 (2d), 128.23 (d),
128.48 (2d), 135.87 (s), 138.75 (s), 143.83 (d, JC-P 14.08), 147.83
(d), 156.16 (d, J 13.07), 169.36 (s), 172.90 (s), 173.10 (s); δP
27.69; m/z (%) 844 (100) [MHϩ], 784 (25) [Mϩ Ϫ OAc].
ethyl acetate as the eluent to give 0.03 g (4.5%) of 20 as an oil
(Found: C, 33.14; H, 3.83; I, 36.91; N, 5.40; P, 3.03. C28H42I3-
N4O11P requires C, 32.90; H, 4.14; I, 37.24; N, 5.48; P, 3.03%);
δH 1.43–1.46 (24 H, 2s), 2.03 (3 H, s), 2.18–2.52 (1 H, m), 2.73–
2.94 (1 H, m), 3.67–3.77 (6 H, 2d), 4.34 (2 H, m), 5.12
(2H = 2(NH), br d, J 6), 6.68 (1 H, m), 8.80 (2H = 2(Ar-NH),
br d, J 8); δC 17.52 (2q), 20.55 (q), 28.27 (6q), 32.36 (dt, JC-P
139.33), 51.01 (2d), 52.63 (2q), 67.97 (d), 80.64 (2s), 107.50 (s),
114.79 (2s), 128.06 (s), 128.51 (s), 134.39 (s), 155.77 (2s), 169.51
(s), 170.80 (2s); δP 28.57; m/z (%) 900 (10) [MHϩ Ϫ CH2-
PO3Me2], 835 (10) [Mϩ Ϫ NHCOCH(Me)NHCO2CMe3], 735
(28) [835 Ϫ CMe3 Ϫ Ac], 734 (32), 732 (50), 648 (30) [Mϩ Ϫ
2NHCOCH(Me)NHCO2CMe], 566 (40), 559 (85) [MHϩ Ϫ
(2 × 187) Ϫ OAc Ϫ OMe].
Dimethyl 2-acetoxy-2-(2,6-diiodo-3,5-diacetamidophenyl)ethyl-
phosphonate 21
Dimethyl 2-acetoxy-2-{2,6-diiodo-3,5-bis[N-(benzyloxycarb-
onyl)glycylamino]phenyl}ethylphosphonate 18
Acetic anhydride (0.038 ml, 0.40 mmol) was added to a stirred
solution of compound 13 (0.05 g, 0.09 mmol) in dry pyridine.
The reaction mixture was stirred for 48 h at room temperature.
The solvent was evaporated under reduced pressure. The resi-
due was dissolved in chloroform, washed twice with cold solu-
tion of 2 M HCl, dried with anhydrous MgSO4, filtered and the
solvent was evaporated under reduced pressure to give 0.09 g
(90%) of 21 as a yellow oil (Found: C, 30.53; H, 3.17; I, 40.54;
N, 4.96. C16H21I2N2O7P requires C, 30.12; H, 3.32; I, 39.77; N,
4.39; P, 4.85%); IR(neat): ν/cmϪ1 3350, 2925, 1744, 1610, 1437,
1371, 1239, 1033; δH 2.07 (3 H, s), 2.23 (6 H, s), 2.34–2.51 (1 H,
m), 2.74–2.96 (1 H, m), 3.71 (3 H, d, J 10), 3.73 (3 H, d, J 10),
6.72 (1 H, m), 7.73 (2 H, br s), 9.08 (1 H, s); δC 20.55 (q), 24.57
(2q), 28.11 (dt, JC-P 140.84), 52.57 (2q), 67.93 (d), 116.23 (d),
133.75 (d, JC-P 11.06), 134.22 (2s), 168.20 (2s), 169.38 (s); δP
28.06; m/z (%) 456 (5) [Mϩ Ϫ OAc Ϫ CH2PO3Me2], 419 (62),
377 (13), 359 (40), 317 (38) [MHϩ Ϫ 127 Ϫ 109 Ϫ 2 × Ac], 109
(39) [PO3Me2], 43 (100) [Ac].
A solution of isobutyl chloroformate (0.35 ml, 2.70 mmol) and
N-methylmorpholine (0.29 ml, 2.70 mmol) in dry THF (25 ml)
cooled to Ϫ20 ЊC (CO2–CCl4 bath) and stirred at this temper-
ature for 20 min. A solution of 13 (0.15 g, 0.27 mmol) in dry
THF (5 ml) was then introduced dropwise over 20 min, and
the reaction mixture was further stirred for another 1–1.5 h at
Ϫ20 ЊC, followed by additional 12 h at room temperature. The
reaction mixture was then filtered, and the solvent was evapor-
ated under reduced pressure. The residue was dissolved in
CH2Cl2, washed in 0.2 M HCl solution, then with 5% NaHCO3
solution and then with brine. The organic phase was dried using
anhydrous MgSO4, filtered, and the solvent was evaporated
under reduced pressure. The residue was purified by chrom-
atography (alumina) using a 10% solution of methanol in ethyl
acetate as the eluent, to give 0.26 g (35%) of 18 as a yellow oil
(Found: C, 41.36; H, 4.11; I, 26.83; N, 6.12. C32H35I2N4O11P
requires C, 41.04; H, 3.77; I, 27.10; N, 5.98; P, 3.31%); IR(neat):
ν/cmϪ1 3350, 1698, 1509, 1420, 1239, 1037, 760; δH 2.04 (3 H, s),
2.13–2.45 (1 H, m), 2.66–2.87 (1 H, m), 3.69 (3 H, d, J 10), 3.70
(3 H, d, J 12), 4.00 (4 H, d, J 6), 5.14 (4 H, s), 6.16 (2 H, br s),
6.63 (1 H, m), 7.33 (10 H, s), 8.57 (2 H, br s), 9.06 (1 H, s);
δC 20.58 (q), 27.98 (dt, JC-P 139.83), 45.68 (2t), 52.38–52.73 (2q),
67.28 (2t), 67.95 (d), 114.89 (d), 128.08 (4d), 128.19 (2d), 128.47
(4d), 133.68 (s), 136.01 (2s), 156.86 (2s), 167.93 (2s), 169.85 (s);
δP 27.93; m/z (%) 772 (100) [Mϩ Ϫ CH2NHCO2CH2Ph].
References
1 (a) D. Parker, Chem. Br., 1994, 818; (b) P. Hannu, U. Pakka and
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8 H. Shalem, S. Shatzmiller and B. A. Feit, Liebigs Ann., 1995, 433.
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Vol. 2, 196; (b) G. H. Woolett and W. W. Johnson, Org. Synth., 1943,
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V. DeCamp, J. Am. Chem. Soc., 1953, 75, 1107.
10 J. E. Siggins, A. A. Larsen, J. H. Ackerman and C. D. Carabateas,
Org. Synth., 1968, 53, 52.
Dimethyl 2-acetoxy-2-{2,4,6-triiodo-5-amino-3-[N-(benzyloxy-
carbonyl)glycylamino]phenyl}ethylphosphonate 19
This compound was prepared analogously to 18 from N-Cbz-
glycine (0.27 g, 1.32 mmol) and compound 12 (0.20 g, 0.29
mmol) to yield 0.01 g (3%) of 19 as an oil (Found: C, 30.01;
H, 3.12; I, 44.03; N, 4.80. C22H25I3N3O8P requires C, 30.33; H,
2.89; I, 43.70; N, 4.82; P, 3.56%); δH 2.03 (3 H, s), 2.17–2.50
(1 H, m), 2.75–2.96 (1 H, m), 3.71 (3 H, d, J 10), 3.72 (3 H, d,
J 10), 3.96 (2 H, d, J 6), 4.31 (-NH2, br s), 5.14 (2H, s), 5.76
(-NH, br s), 6.64 (1 H, m), 7.32 (5 H, 2), 8.45 (Ar-NH, br s);
δC 20.66 (q), 28.20 (dt, JC-P 140.33), 46.00 (t), 52.55 (2q), 67.61
(t), 68.02 (d), 87.24 (s), 107.48 (2s), 128.23 (2d), 128.42 (d),
128.59 (2d), 143.04 (s), 150.47 (s), 155.68 (s), 169 (s), 178.61 (s);
δP 28.47; m/z (%) 871 (10) [Mϩ], 855 (5) [Mϩ Ϫ NH2], 664 (15)
[Mϩ Ϫ NHCOCH2NHCO2CH2Ph], 662 (17), 621 (20) [664 Ϫ
Ac], 605 (25) [664 Ϫ OAc], 598 (25), 583 (80) [MHϩ Ϫ NHCO2-
CH2Ph Ϫ CH2PO3Me2 Ϫ 16], 581 (100) [MHϩ Ϫ CH2NHCO2-
CH2Ph Ϫ 127], 579 (75), 562 (43).
11 M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis,
Springer-Verlag, Berlin, Heidelberg, New York, Tokyo, 1984, 177.
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13 M. Sovak, T. Almén, K. Golman and J. A. Nelson, Radiocontrast
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Dimethyl 2-acetoxy-2-{2,4,6-triiodo-3,5-bis[N-tert-butoxy-
carbonyl)alanylamino]phenyl}ethylphosphonate 20
This compound was prepared analogously to 18 from t-Boc-
alanine (0.41 g, 2.20 mmol) and compound 12 (0.15 g, 0.22
mmol). The residue obtained after work-up was purified by
chromatography (alumina) using a 5% solution of methanol in
J. Chem. Soc., Perkin Trans. 1, 2000, 2831–2837
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