CDCl3): d 177.2, 172,5, 170.3, 167.2, 157.4, 154.9, 145.1, 140.0,
137.6, 132.5, 130.3, 129.8, 124.8, 120.3, 108.2, 105.4, 68.5, 51.3,
50.7, 45.3, 43.2, 30.4, 29.8, 18.1. 19F NMR (400 MHz, CDCl3): d
-122.6 (s, 1F), -152.6 – - 151.8 (m, 2F), -157.4 (t, J = 22 Hz, 1F),
-162.7 – - 162.5 (m, 2F). MS (ESI): m/z 614.1 [M+H+].
7.40–7.27 (m, 2H), 6.99–6.79 (m, 2H), 5.05–4.99 (m, 1H), 4.82–
4.77 (m, 3H), 4.32–4.13 (m, 2H), 3.65–3.58 (m, 1H), 3.54–3.07
(m, 4H), 1.71–1.62 (m, 2H). 13C NMR (100 MHz, (CD3)2CO): d
173.7, 159.1, 156.2, 155.6, 133.7, 130.8, 119.4, 117.4, 72.2, 66.6,
59.9, 36.7, 34.9, 32.2, 29.9. MS (ESI): m/z 368.1 [M+H+].
Succinic acid 4-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-
dihydro-quinolin-7-yl)-piperazine-1-carbonyloxymethyl ester
pentafluorophenyl ester 32
General procedure for the synthesis of pyochelin–fluoroquinolone
conjugates 35 to 40
Rf 0.68 (CH2Cl2–EtOH 95 : 5). 1H NMR (400 MHz, DMSO-d6):
d 8.96 (s, 1H), 7.93 (d, J = 13 Hz, 1H), 7.19 (d, J = 7 Hz, 1H), 5.76
(s, 2H), 3.60 (t, J = 6 Hz, 4H), 3.37–3.27 (m, 5H), 3.08–3.05 (m,
2H), 2.83–2.78 (m, 4H), 1.42–1.39 (m, 4H). 13C NMR (100 MHz,
DMSO-d6): d 176.3, 171.3, 168.6, 165.8, 152.7, 148.1, 144.8, 139.1,
135.3, 129.4, 111.0, 106.7, 80.3, 49.04, 43.3, 43.0, 35.8, 28.6, 28.3,
27.8, 7.58. 19F NMR (400 MHz, DMSO-d6): d -121.7 (s, 1F),
-153.1 – - 153.2 (m, 2F), -157.9 (t, J = 25 Hz, 1F), -162.6 –
- 162.8 (m, 2F). MS (ESI): m/z 672.1 [M+H+].
Functionalized pyochelin 9 (1.00 mmol) and DIPEA (2.00 mmol)
were successively added to a solution of pentafluorophenyl ester
14, 15, 21, 32, 33 or 34 (1.40 mmol) in CH2Cl2 (15 mL). The
solution was stirred at 20 ◦C for 12 h. The mixture was washed with
0.5 N HCl, water and brine. The organic layer was collected, dried
over Na2SO4, filtered and evaporated under reduced pressure. The
crude product was purified by chromatography on a silica gel
column (CH2Cl2–EtOH 99 : 1 to 98 : 2), leading to the expected
pyochelin–fluoroquinolone conjugates 35 (429 mg, 0.55 mmol,
55%), 36 (333 mg, 0.39 mmol, 39%), 37 (576 mg, 0.75 mmol,
75%), 38 (522 mg, 0.62 mmol, 62%), 39 (494 mg, 0.62 mmol, 62%)
and 40 (861 mg, 0.99 mmol, 99%).
Succinic acid 4-(3-carboxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-
quinolin-7-yl)-piperazine-1-carbonyloxymethyl ester
pentafluorophenyl ester 33
1
Rf 0.54 (CH2Cl2–EtOH 95 : 5). H NMR (400 MHz, CDCl3): d
7-[4-(3-{3-[4-Carboxy-2¢-(2-hydroxy-phenyl)-4,5,4¢,5¢-tetrahydro-
[2,4¢]bithiazolyl-3-yl]-propylcarbamoyl}-propionyl)-piperazin-1-
yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid 35
8.69 (s, 1H), 8.10 (d, J = 13 Hz, 1H), 6.83 (d, J = 7 Hz, 1H), 5.85
(s, 2H), 4.31 (q, J = 7 Hz, 2H), 3.73 (br s, 4H), 3.28 (br s, 4H), 3.03
(dd, J = 6, 5 Hz, 2H), 2.85 (dd, J = 6, 5 Hz, 2H), 1.59 (t, J = 7 Hz,
3H). 13C NMR (CDCl3, 100 MHz): d 177.1; 170.7; 168.4; 167.3;
159.9; 153.6; 153.4; 147.4; 145.8; 137.1; 121.2; 113.1; 108.5; 104.4;
80.8; 49.9; 49.7; 43.9; 43.6; 28.8; 28.2; 14.6. 19F NMR (CDCl3, 400
MHz): d -121.9 (s, 1F), -153.1 – - 153.2 (m, 2F), -158.0 (t, J = 24
Hz, 1F), -162.6 – - 162.7 (m, 2F). MS (ESI): m/z 660.1 [M+H+].
1
Rf 0.76 (CH2Cl2–EtOH 95 : 5). H NMR (400 MHz, CDCl3): d
8.73 (d, J = 4 Hz, 1H), 8.01 (d, J = 13 Hz, 1H), 7.37–7.30 (m,
3H), 6.93 (d, J = 8 Hz, 1H), 6.83 (br t, J = 8 Hz, 1H), 6.24 (br s,
1H), 4.83–4.77 (m, 1H), 4.25–4.12 (m, 3H), 3.82 (br s, 3H), 3.72
(br s, 3H), 3.35–3.27 (m, 9H), 2.70 (t, J = 6 Hz, 2H), 2.52 (t, J =
6 Hz, 2H), 1.92–1.84 (m, 3H), 1.40–1.31 (m, 4H). 13C NMR (100
MHz, CDCl3): d 186.8, 177.3, 172.6, 170.7, 167.1, 159.4, 156.8,
151.5, 147.8, 144.2, 138.9, 133.5, 130.8, 119.1, 117.3, 112.9, 108.6,
105.4, 81.7, 71.3, 71.3, 64.8, 64.5, 63.4, 50.1, 45.3, 41.6, 41.0, 37.7,
35.5, 34.5, 31.3, 29.9, 28.7, 22.9, 14.3, 8.51. MS (ESI): m/z 781.2
[M+H+]. HRMS (ESI): C37H41FN6O8S2: calcd 780.24113, found
780.24057.
Succinic acid 4-(5-carboxy-8-fluoro-3-methyl-6-oxo-2,3-dihydro-
6H-1-oxa-3a-aza-phenalen-9-yl)-piperazine-1-carbonyloxymethyl
ester pentafluorophenyl ester 34
Rf 0.70 (CH2Cl2–EtOH 9 : 1). 1H NMR (400 MHz, CDCl3): d 8.57
(s, 1H), 7.67 (d, J = 12 Hz, 1H), 5.76 (s, 2H), 4.53–4.49 (m, 1H),
4.40 (ddd, J = 25, 11, 2 Hz, 2H), 3.66 (s, 4H), 3.32 (br s, 4H),
2.60–2.45 (m, 4H), 1.60 (d, J = 4 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d 177.4, 175.8, 169.1, 165.4, 151.7, 143.7, 138.5, 135.1,
131.1, 123.4, 121.1, 117.5, 106.4, 104.2, 83.6, 81.6, 71.1, 68.5, 55.7,
50.2, 45.3, 44.6, 44.0, 39.1, 34.3, 29.8, 26.1, 18.5. 19F NMR (CDCl3,
400 MHz): d -124.2 (s, 1F), -153.1 – - 153.2 (m, 2F), -160.0 (t,
J = 24 Hz, 1F), -164.2 – - 164.3 (m, 2F). MS (ESI): m/z 703.1
[M+H+]
7-[4-(3-{3-[4-Carboxy-2¢-(2-hydroxy-phenyl)-4,5,4¢,5¢-tetrahydro-
[2,4¢]bithiazolyl-3-yl]-propylcarbamoyl}-propionyloxymethoxy-
carbonyl)-piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-
dihydro-quinoline-3-carboxylic acid 36
1
Rf 0.49 (CH2Cl2–EtOH 98 : 2). H NMR (400 MHz, CDCl3): d
Synthesis of 3-(3-amino-propyl)-2¢-(2-hydroxy-phenyl)-
2,3,4,5,4¢,5¢-hexahydro-[2,4¢]bithiazolyl-4-carboxylic acid 9
8.66 (s, 1H), 7.92 (d, J = 13 Hz, 1H), 7.36–7.24 (m, 3H), 6.93–
6.81 (m, 2H), 6.13–6.07 (m, 1H), 5.78 (s, 2H), 4.80–4.75 (m, 1H),
4.24–4.09 (m, 3H), 3.71 (br s, 4H), 3.55–3.42 (m, 4H), 3.35–3.26
(m, 7H), 2.72–2.67 (m, 3H), 2.47 (q, J = 7 Hz, 2H), 1.88–1.82 (m,
2H), 1.37–1.25 (m, 4H). 13C NMR (100 MHz, CDCl3): d 177.1,
173.5, 172.1, 171.4, 167.1, 159.2, 153.6, 152.4, 147.7, 145.3, 139.1,
133.5, 130.8, 120.2, 119.1, 116.2, 112.6, 108.2, 105.4, 81.6, 80.8,
71.3, 64.5, 63.3, 49.8, 49.6, 44.1, 43.7, 37.9, 36.4, 35.5, 34.7, 30.8,
29.9, 29.6, 28.8, 27.1, 8.44. MS (ESI): m/z 855.2 [M+H+]. HRMS
(ESI): C39H43FN6O11S2: calcd 854.24153, found 854.24150.
Pyochelin analog 4 (148 mg, 0.31 mmol) was dissolved in a
mixture of CH2Cl2–TFA 8 : 2 (3 mL) and stirred 4 h at 20 ◦C.
The mixture was evaporated to dryness under reduced pressure
and then dissolved in CH2Cl2. The organic layer was washed with
water and brine, dried over Na2SO4, filtered and evaporated under
reduced pressure. The resulting yellow oil was triturated with Et2O
to give amine 9 (116 mg, 0.31 mmol, 100%) as a yellow solid. Rf
1
0.16 (CH2Cl2–EtOH 9 : 1). H NMR (400 MHz, (CD3)2CO): d
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 8288–8300 | 8297
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