1
3
yellow solid (12 mg, 26%). HPLC: RT = 27.40 min. H NMR
(300 MHz, CDCl3), d 8.18 (2H, dd, Ar), 7.48 (1H, d, JH–H
=
3
(270 MHz, D2O), d 270.0 (1H), 216.5 (1H), 205.6 (1H), 168.9
(1H), 151.1 (1H), 121.4 (1H), 101.5 (1H), 82.5 (3H), 78.4 (3H),
63.2 (3H), 42.8 (3H), 12.2 (2H), −0.4 (2H), −31.6 (1H) −73.6
(1H), −80.8 (1H), −82.2 (1H), −83.7 (1H), −94.9 (1H), −114.6
(1H), −117.8 (2H), −142.1 (1H), −412.7 (1H), −438.5 (1H),
−479.1 (1H), −500.1 (1H). m/z (ESMS EI−): 750 (100%, [M−])
the appropriate isotope pattern was observed.
8 Hz, Ar), 7.37 (1H, d, JH–H = 8 Hz, Ar), 3.77–2.05 (34H, m
br), 1.18 (9H, m, CHCH3). 13C NMR (75.5 MHz, CDCl3), d 7.1
(Me), 7.8 (Me), 30.7, 31.1, 32.3, 41.6, 44.4, 44.7, 45.1, 46.4, 48.6,
50.4, 51.8, 52.1, 52.3, 53.3, 56.0, 56.3, 60.3, 61.2, 121.8 (br, Ar),
=
130.3 (br, Ar), 146.3 (br, Ar) 147.9 (br, Ar), 174.2 (C O), 175.8
+
=
=
(C O), 176.1 (C O). m/z (ESMS EI+): 638 (5%, [M + H ]),
660 (100%, [M + Na+]), 674 (15%, [M + K+]), mmax/cm−1: 2953,
=
2844, 1728 (C O), 1519, 1344, 1260, 1222, 1132, 1030. Anal.
Trimethyl-(4S,7S,10S)-a,aꢀ,aꢀꢀ -trimethyl[(S)-2-(nitrobenzyl)]-
Found C, 47.1; H, 6.1; N, 8.6. C30H47N5O10·2CH2Cl2 requires C,
1,4,7,10-tetraazacyclododecane-4,7,10-triacetate
(S-SSS-7).
47.6; H, 6.4; N, 8.7%.
(S)-2-(Nitrobenzyl)cyclen 3 (1.0 g, 3.26 mmol) and triethylamine
(1.27 g, 12.56 mmol) were dissolved in dry acetonitrile (10 mL),
under an argon atmosphere and cooled to 0 ◦C. (R)-Methyl
O-trifluoromethanesulfonyl lactate 6 (2.97 g, 12.56 mmol)22 was
added dropwise over a period of 10 min. The reaction was then
warmed to room temperature and stirred for 4 days at ambient
temperature. The solvents were the removed under reduced
pressure. The residue was taken up into dichloromethane
(150 mL) and water (30 mL) and the two layers separated. The
aqueous layer was extracted with dichloromethane (50 mL)
and the organic extracted combined, dried (Na2SO4), and the
solvents removed under reduced pressure. The orange–brown
residue was purified by dry-flash column chromatography over
silica gel eluting with 5% methanol in dichloromethane. After
drying under high vacuum the title compound was obtained
as a orange oil (1.78 g, 96%). Rf = 0.3 (5% MeOH in CH2Cl2,
SiO2). 1H NMR (300 MHz, CDCl3), 8.08 (2H, d, 3JH–H = 8 Hz,
Tetramethyl-(4R,7R,10R) -a,aꢀ,aꢀꢀ-trimethyl[(S)-2-(nitrobenzyl)]-
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (S-RRR-
8). The title compound was synthesized from S-RRR-7 ac-
cording to the protocol used for S-SSS-8. The title compound
was obtained as a brownish orange solid (0.4 g, 28%); mp
129–131 C, Rf = 0.3 (2% MeOH in CH2Cl2, SiO2). H NMR
(300 MHz, CDCl3), d 8.03 (2H, d, 3JH–H = 8 Hz, Ar), 7.38 (2H, d,
3JH–H = 8 Hz, Ar), 3.8–2.3 (34 H, m br), 1.17 (9H, m, CHCH3).
13C NMR (75.5 MHz, CDCl3), d 14.9 (Me), 15.5 (2 × Me), 33.5,
35.2, 44.9, 46.7, 47.3, 49.2, 49.9, 51.2, 51.6, 51.9, 52.5, 55.7, 56.4,
57.7, 60.4, 123.3 (Ar), 130.1 (Ar), 146.1 (Ar), 147.6 (Ar), 172.3
◦
1
=
=
=
(C O), 174.5 (2 × C O), 175.6 (C O). m/z (ESMS EI+): 638
(35%, [M + H+]), 660 (100%, [M + Na+], mmax/cm−1: 2949, 2845,
=
1727 (C O), 1517, 1433, 1343, 1199, 1138, 1052.
(4S,7S,10S)-a,aꢀ,aꢀꢀ -Trimethyl[(S)-2-(nitrobenzyl)]-1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetraacetic acid (S-SSS-2).
The tetramethyl ester S-SSS-8 (130 mg, 0.36 mmol) was
dissolved in THF (5 mL). A 1 M solution of sodium hydroxide
(1.8 mL) and water (5 mL) was added and the reaction stirred
at 55 ◦C for 24 h. After cooling, the solvents were removed
under reduced pressure. The residue was dissolved in water
(5 mL) and purified by HPLC (97 mg, 82%); mp: decomposes
>180 ◦C, HPLC: RT = 27.98 min. 1H NMR (300 MHz,
3
Ar), 7.52 (2H, d, JH–H = 8 Hz, Ar), 3.72–2.31 (29H, m br),
1.34–1.04 (9H, m br, CHCH3). 13C NMR (75.5 MHz, CDCl3),
d 8.3 (Me), 8.5 (Me), 8.7 (Me), 34.8, 46.2 (br), 49.0 (br), 50.8,
51.0, 51.3, 53.7, 54.3, 56.4, 59.0 (br), 66.1, 123.8 (Ar), 130.3
=
=
(Ar), 143.8 (Ar), 147.1 (Ar), 167.9 (C O), 173.6 (C O), 173.8
+
(C O). m/z (ESMS EI+): 566 (100%, [M + H ]), mmax/cm−1:
=
=
2952, 2852, 1729 (C O), 1519, 1456, 1346, 1240, 1222, 1153,
1028.
CDCl3), d 8.08 (2H, d, 3JH–H = 8 Hz, Ar), 7.48 (2H, d, 3JH–H
=
3
8 Hz, Ar), 4.6–2.5 (22H, m br), 1.57 (3H, d, JH–H = 6 Hz,
Trimethyl-(4R,7R,10R)-a,aꢀ,aꢀꢀ-trimethyl[(S)-2-(nitrobenzyl)]-
3
3
CH3), 1.45 (3H, d, JH–H = 6 Hz, CH3), 1.25 (3H, d, JH–H
=
1,4,7,10-tetraazacyclododecane-4,7,10-triacetate
(S-RRR-7).
6 Hz, CH3). 13C NMR (75.5 MHz, CDCl3), d 10.6 (Me), 11.6
(Me), 11.9 (Me), 33.6, 34.3, 45.6, 47.1, 49.4, 50.0, 50.8, 51.0,
51.4, 52.0, 53.2, 53.3, 55.2, 57.9, 62.6, 61.9, 126.6 (Ar), 132.8
The title compound was synthesized using the same protocol as
S-SSS-7 using S-methyl O-trifluoromethanesulfonyl lactate 6.22
The title compound was obtained as a orange oil (1.6 g, 89%).
=
=
(Ar), 147.5 (Ar), 148.9 (Ar), 173.7 (2 × C O), 176.9 (C O),
1
Rf = 0.3 (5% MeOH in CH2Cl2, SiO2). H NMR (300 MHz,
2−
=
179.1 (C O). m/z (ESMS EI−): 309 (26%, [HL + K] ), 618
CDCl3), d 8.01 (2H, d, 3JH–H = 9 Hz, Ar), 7.53 (2H, d, 3JH–H
=
(100%, [H2L + K]−), mmax/cm : 1716 (C O), 1645, 1519, 1456,
−1
=
3
9 Hz, Ar), 3.73–2.35 (29H, m), 1.26 (3H, d, JH–H = 8 Hz,
1394, 1349, 1251, 1107. Anal. Found: C, 42.3; H, 7.1; N, 9.5.
3
CHCH3), 1.23 (3H, d, JH–H = 8 Hz, CHCH3), 1.16 (3H, d,
C27H39N5O10·4H2O·2.5HCl requires C, 41.9; H, 6.7; N, 9.4%.
3JH–H = 7 Hz, CHCH3). 13C NMR (75.5 MHz, CDCl3), d 9.9
(Me), 13.4 (Me), 15.7 (Me), 35.5, 45.4, 46.6, 47.6, 48.4, 51.3,
51.5, 51.7, 52.0, 53.6, 56.1, 57.8, 58.4, 58.5, 123.7 (Ar), 130.4
(4R,7R,10R)-a,aꢀ,aꢀꢀ -Trimethyl[(S)-2-(nitrobenzyl)]-1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetraacetic acid (S-RRR-2).
The title compound was prepared from S-RRR-8 according to
the procedure employed for S-SSS-2. The complex was isolated
after removal of the solvents by lyopholization to afford a
pale yellow solid (120 mg, 62%). HPLC: RT = 27.77 min, mp
=
=
(Ar), 143.7 (Ar), 146.9 (Ar), 173.3 (C O), 173.7 (C O), 174.1
+
=
(C O). m/z (ESMS EI+): 566 (100%, [M + H ]), 587 (5%,
[M + Na+], mmax/cm : 2952, 2847, 1728 (C O), 1596, 1519,
−1
=
1356, 1204, 1131, 1030, 972.
223–225 ◦C. 1H NMR (300 MHz, CDCl3), d 8.07 (2H, d, 3JH–H
=
Tetramethyl-(4S,7S,10S)-a,aꢀ,aꢀꢀ-trimethyl[(S)-2-(nitrobenzyl)]-
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (S-SSS-
8). The triester S-SSS-7 (1.65 g, 2.91 mmol) was dissolved
in acetonitrile (10 mL) under argon. Potassium carbonate
(0.44 g, 3.2 mmol) and methyl bromoacetate (0.49 g, 3.2 mmol)
were added. The reaction mixture was stirred, under argon
at 60 ◦C for 4 days. The solvents were then removed under
reduced pressure and the residue taken up into dichloromethane
(150 mL) and water (30 mL). The two layers were separated and
the aqueous layer extracted with dichloromethane (50 mL). The
organic layers were combined, dried (Na2SO4), and the solvents
removed under reduced pressure. The residue was purified by
dry flash column chromatography over silica gel eluting with
2% methanol in dichloromethane. After drying under vacuum
the title compound was obtained as a brownish orange oil
which was found to solidify on standing (0.74 g, 40%); mp
7 Hz, Ar), 7.46 (2H, d, 3JH–H = 7 Hz, Ar), 4.4–2.8 (22H, m br),
3
3
1.58 (3H, d, JH–H = 6 Hz, CH3), 1.48 (3H, d, JH–H = 6 Hz,
CH3), 1.31 (3H, d, 3JH–H = 6 Hz, CH3). 13C NMR (75.5 MHz,
CDCl3), d 13.8 (Me), 15.3 (Me), 15.5 (Me), 35.0, 46.7, 48.6,
50.6, 51.1, 54.4, 57.8, 58.1, 60.7, 62.9, 63.5, 65.2, 125.5 (Ar),
=
131.8 (Ar), 147.4 (Ar), 149.0 (Ar), 173.6 (2 × C O), 178.0
=
=
(C O), 178.8 (C O). m/z (ESMS EI−): 309 (100%, [HL +
K]2−), 618 (18%, [H2L + K]−), mmax/cm−1: 3343, 2992,2863, 1720
=
(C O), 1599, 1517, 1468, 1398, 1346, 1225, 1181, 1103.
(4S,7S,10S)-a,aꢀ,aꢀꢀ -Trimethyl[(S)-2-(nitrobenzyl)]-1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetraacetate europium(III) com-
plex (H[Eu(S-SSS-2)]). S-SSS–2 (121 mg, 0.18 mmol) was
dissolved in water (3 mL). A solution of europium chloride
hexahydrate (46 mg, 0.18 mmol) in water (3 mL) was added and
the reaction stirred at 60 ◦C for 24 h. After cooling, the solution
was filtered through a 40 lm syringe filter and then purified by
◦
1
216–218 C, Rf = 0.3 (2% MeOH in CH2Cl2, SiO2). H NMR
3 8 3 6
D a l t o n T r a n s . , 2 0 0 5 , 3 8 2 9 – 3 8 3 7