3312 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 14
Bergeron et al.
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dicarboxylate (2.53 g, 12.50 mmol) were successively added to a
solution of 11 (3.0 g, 10.16 mmol) and triphenylphosphine (3.17
g, 12.09 mmol) in dry THF (60 mL) with ice bath cooling. The
solution was stirred at room temperature for 8 h and was maintained
at 5 °C for 40 h. Solvent was removed by rotary evaporation, and
40% EtOAc/petroleum ether (50 mL) was added. The solution was
kept at 5 °C for 12 h; the solid formed was filtered. The filtrate
was concentrated in vacuo and was purified by column chroma-
tography eluting with 50% EtOAc/petroleum ether to give 1.08 g
of 13 (25%) as an orange oil. An analytical sample was purified
on C-18 reverse phase column eluting with equal volumes of 50%
aq MeOH and 40% aq MeOH, respectively: [R]20 +40.0°; 1H NMR
δ 1.30 (t, 3 H, J ) 7.2), 1.66 (s, 3 H), 3.23 (d, 1 H, J ) 11.2), 3.38
(s, 3 H), 3.52-3.58 (m, 2 H), 3.63-3.71 (m, 4 H), 3.74-3.79 (m,
2 H), 3.88 (d, 1 H, J ) 11.6), 3.91 (t, 2 H, J ) 5.0), 4.20-4.26
(m, 4 H), 6.79 (t, 1 H, J ) 7.6), 7.01-7.07 (m, 2 H); 13C NMR δ
14.18, 24.47, 39.96, 59.10, 62.07, 68.95, 69.79, 70.60, 70.70, 70.91,
71.99, 83.48, 116.42, 117.62, 118.29, 122.71, 147.72, 150.35,
171.70, 172.69; HRMS m/z calcd for C20H29NO7SNa, 450.1562 (M
+ Na); found, 450.1568. Anal. (C20H29NO7S) C, H, N.
(6) Lieu, P. T.; Heiskala, M.; Peterson, P. A.; Yang, Y. The Roles of
Iron in Health and Disease. Mol. Aspects Med. 2001, 22, 1-87.
(7) Angelucci, E.; Brittenham, G. M.; McLaren, C. E.; Ripalti, M.;
Baronciani, D.; Giardini, C.; Galimberti, M.; Polchi, P.; Lucarelli,
G. Hepatic Iron Concentration and Total Body Iron Stores in
Thalassemia Major. N. Engl. J. Med. 2000, 343, 327-331.
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LiVer Dis. 2000, 4, 409-429, vi-vii.
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and â-Cell Secretion in Thalassaemia Major with Secondary Haemo-
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J. W. Efficacy of Deferoxamine in Preventing Complications of Iron
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of Transferrin and Ferritin. Semin. Hematol. 1998, 35, 35-54.
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(S)-4,5-Dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-
4-methyl-4-thiazolecarboxylic Acid (9). A solution of 50% (w/
w) NaOH (13.88 mL, 266.02 mmol) in CH3OH (120 mL) was
added to 13 (8.89 g, 20.80 mmol) in CH3OH (280 mL) with ice
bath cooling. The reaction mixture was stirred at room temperature
for 6 h, and the bulk of the solvent was removed by rotary
evaporation. The residue was treated with dilute NaCl (300 mL),
and the basic aqueous phase was cooled in ice, acidified with 2 N
HCl to pH ) 2, and extracted with EtOAc (4 × 150 mL). After
the EtOAc layers were washed with saturated NaCl (300 mL),
glassware that was presoaked in 3 N HCl for 15 min was employed
henceforth. After solvent removal by rotary evaporation, purification
was done on C-18 reverse phase column, eluting with 50% aq
methanol and lyophilized to furnish 4.98 g of 9 (60%) as an orange
1
oil: [R]20 +61.9°; H NMR (D2O) δ 1.77 (s, 3 H), 3.35 (s, 3 H),
3.56-3.62 (m, 3 H), 3.64-3.73 (m, 4 H), 3.75-3.89 (m, 2 H),
3.92-3.96 (m, 2 H), 3.99 (d, 1 H, J ) 11.6), 4.25-4.31 (m, 2 H),
6.99 (t, 1 H, J ) 8.2), 7.26-7.33 (m, 2 H); 13C NMR δ 24.52,
39.93, 59.07, 69.04, 69.83, 70.49, 70.64, 70.86, 71.97, 83.21,
116.33, 117.94, 118.50, 122.80, 147.67, 150.24, 172.38, 176.10;
HRMS m/z calcd for C18H26NO7S, 400.1429 (M + H); found,
400.1413.
(22) Halliwell, B. Iron, Oxidative Damage, and Chelating Agents. In The
DeVelopment of Iron Chelators for Clinical Use; Bergeron, R. J.,
Brittenham, G. M., Eds.; CRC: Boca Raton, 1994; pp 33-56.
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Implications for Iron Toxicity. In Iron Chelators: New DeVelopment
Strategies; Badman, D. G., Bergeron, R. J., Brittenham, G. M., Eds.;
Saratoga: Ponte Vedra Beach, FL, 2000; pp 3-10.
Acknowledgment. Funding was provided by the National
Institutes of Health Grant No. R37-DK49108. We thank
Elizabeth M. Nelson, Tanaya Lindstrom, and Katie Ratliff-
Thompson for their technical assistance and Carrie A. Blaustein
for her editorial and organizational support. The authors
gratefully acknowledge the National Science Foundation for
funding through the National High Magnetic Field Laboratory,
which supported our NOE difference studies at the Advanced
Magnetic Resonance Imaging and Spectroscopy (AMRIS)
facility in the McKnight Brain Institute of the University of
Florida.
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Biol. Med. 1992, 13, 169-181.
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J. W. Human Neutrophils Employ the Myeloperoxidase-Hydrogen
Peroxide-Chloride System to Oxidize R-Amino Acids to a Family
of Reactive Aldehydes. Mechanistic Studies Identifying Labile
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McManis, E. Iron Chelators and Therapeutic Uses. In Burger’s
Medicinal Chemistry, 6th ed.; Abraham, D. A., Ed.; Wiley: New
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An Optimistic Update. Semin. Hematol. 2001, 38, 360-366.
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Supporting Information Available: Elemental analytical data
for synthesized compounds. This material is available free of charge
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