Total Synthesis of the Siderophore Danoxamine
J . Org. Chem., Vol. 65, No. 16, 2000 4837
dure26 with the minor modification of increasing the 5-chlo-
rovaleronitrle to 1.2 equiv to afford an improved yield of 98%.
N-(5-Am in op en tyl)-N-(ter t-bu toxyca r bon yl)-O-ben zyl-
h yd r oxyla m in e (3) was synthesized by a published proce-
dure26 in 91% yield.
and filtered, and the solvent removed under reduced pressure
to yield a yellow oil. This oil was purified by column chroma-
tography (5% CH3OH/CHCl3) to afford deprotected 17 (0.771
1
g, 99%) as an oil: IR (film, cm-1) 3300, 1640; H NMR (300
MHz, CDCl3) δ 7.30-7.38 (m, 15H), 6.03 (t, J ) 4.80, 1H), 4.84
(s, 2H), 4.69 (s, 2H), 4.48 (s, 2H), 3.63 (4, J ) 6.8, 2H), 3.44 (t,
J ) 6.5, 2H), 3.20 (q, J ) 6.7, 2H), 2.91 (t, J ) 7.1, 2H), 2.78
N-(5-Ben zyloxyp en tyl)-O-ben zylh yd r oxyla m in e (10).
Trifluoroacetic acid (TFA, 15 mL) was added to a solution of 4
(1.50 g, 3.75 mmol) in CH2Cl2 (20 mL). The resulting solution
was stirred at room temperature for 10 min at which time TLC
analysis indicated that the reaction was complete. TFA and
CH2Cl2 were removed under reduced pressure. Saturated
aqueous NaHCO3 was added to the oil, and the product was
extracted into CHCl3. The organic phases were combined and
washed with H2O, dried (MgSO4), and filtered, and the solvent
was removed under reduced pressure to yield hydroxylamine
(t, J ) 6.3, 2H), 2.45 (t, J ) 6.6, 2H), 1.27-1.70 (m, 12H); 13
C
NMR (75 MHz, CDCl3) δ 173.70 (broad), 172.12, 138.52,
137.93, 134.35, 129.08, 128.85, 128.64, 128.30, 127.70, 127.55,
127.42, 76.30, 76.13, 72.81, 70.06, 51.88, 45.55 (broad), 39.35,
30.87, 29.42, 29.32, 28.26, 26.97, 26.67, 24.42, 23.39; HRMS
(FAB) calcd for C35H48N3O5 (M + H) 590.3594, found 590.3593.
Meth od B. The acid 11 (430 mg, 1.08 mmol), amine 1622
(348 mg, 1.24 mmol), DMAP (7.0 mg, 0.05 mmol), CH2Cl2 (20
mL), and Et3N (330 mL, 2.37 mmol) were combined in a round-
bottomed flask. To this solution, under argon, was added EDC‚
HCl (248 mg, 1.29 mmol). The reaction was stirred at room
temperature and followed by TLC (3% i-PrOH in 3:1 EtOAc:
hexanes). After 3 h, CH2Cl2 was added to the reaction and 5%
NaHCO3 was used to wash the organic layer. Brine was used
to further wash the organic layer which was then dried (Na2-
SO4) and filtered, and the solvent was removed under reduced
pressure. The crude material was purified by column chroma-
tography (3% i-PrOH in 3:1 EtOAc:hexanes) to afford a white
solid (431 mg, 68%). The spectra matched those from the
previous preparations of this material.
1
10 (1.101 g, 98%: IR (film, cm-1) 3263; H NMR (300 MHz,
CDCl3) δ 7.36-7.25 (m, 10H), 5.54 (broad s, 1H), 4.70 (s, 2H),
4.49 (s, 2H), 2.46 (t, J ) 6.44 Hz, 2H), 2.93 (t, J ) 7.04 Hz,
2H), 1.67-1.34 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 138.58,
137.97, 128.31, 127.72, 127.57, 127.45, 76.16, 72.86, 70.20,
52.05, 29.60, 27.15, 23.90; HRMS (FAB) calcd for C19H26O2N
(M + H) 300.1964, found 300.1950.
N-(Ben zyloxy)-N-(5-ben zyloxyp en tyl)su ccin a m ic Acid
(11). Hydroxylamine 10 (2.90 g, 9.67 mmol), succinic anhydride
(1.452 g, 14.5 mmol), and a catalytic amount of DMAP was
added to a flask containing pyridine (30 mL). The solution was
heated at 95 °C for 3 h under argon, cooled to room temper-
ature, and stirred at room temperature for 3 days. The pyridine
was removed under vacuum, and the residue was dissolved
in a minimal amount of chloroform and filtered. The chloro-
form was removed under reduced pressure, and the resulting
oil was purified by chromatography (3 to 10% ethanol in
CHCl3) to give a yellow oil (3.803 g, 98%): IR (film, cm-1) 1730,
1700; 1H NMR (300 MHz, CDCl3) δ 9.790 (bs, 1H), 7.25-7.40
(m, 10H), 4.83 (s, 2H), 4.48 (s, 2H), 3.64 (t, J ) 6.90 Hz, 2H),
3.45 (t, J ) 6.30 Hz, 2H), 2.58-2.76 (m, 4H), 1.56-1.72 (m,
4H), 1.32-1.44 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.53,
173.17 (broad), 138.47, 134.31, 129.11, 128.93, 128.68, 128.28,
127.57, 127.43, 76.24, 72.77, 70.05, 45.53 (broad), 29.24, 28.70,
27.21, 26.58, 23.33; HRMS (FAB) calcd for C23H30O5N (M +
H) 400.2124, found 400.2121.
17-(ter t-Bu t oxyca r b on yl)-1,6,17-t r is(b en zyloxy)-7,10-
d ioxo-6,11,17-tr ia za h ep ta d eca n e (12). Acid 11 (5.08 g, 12.7
mmol) was dissolved in distilled CH3CN (50 mL). The resulting
solution was cooled to 0 °C under argon, and diphenylphos-
phorazide (DPPA, 3.02 mL, 14.0 mmol) and triethylamine (3.90
mL, 28.0 mmol) were added to the flask. Amine 3 (4.31 g, 14.0
mmol) dissolved in CH3CN (10 mL) was added dropwise to the
reaction. The solution was stirred in an ice bath at 0 °C for 5
h and then allowed to warm to room temperature. After
stirring at room temperature for 14 h, H2O was added and
the solution was extracted with EtOAc. The organic layers
were combined and washed with brine, dried (Na2SO4), and
filtered, and the was solvent removed under reduced pressure
to yield a yellow oil. The oil was purified by radial chroma-
tography (100% hexanes to 100% EtOAc) to give a yellow oil
(7.99 g, 91%): IR (film, cm-1) 3320, 1650; 1H NMR (300 MHz,
CDCl3/CD3OD) δ 7.26-7.42 (m, 15H), 5.98 (t, J ) 4.5 Hz, 1H),
4.837 (s, 2H), 4.813 (s, 2H), 4.477 (s, 2H), 3.624 (t, J ) 6.3,
2H), 3.44 (t, J ) 6.6 Hz, 2H), 3.40 (t, J ) 7.2 Hz, 2H), 3.20 (q,
J ) 6.9 Hz, 2H), 2.77 (t, J ) 5.70, 2H), 2.44 (t, J ) 6.3 Hz,
2H), 1.15-1.75 (m + s, 21H); 13C NMR (75 MHz, CDCl3) δ
173.8 (broad) 172.16, 156.56, 138.55, 135.600 134.39, 129.34,
129.12, 128.88, 128.66, 128.45, 128.34, 128.31, 127.56, 127.46,
81.18, 76.87, 76.32, 72.84, 70.10, 49.34, 45.59 (broad), 39.40,
30.87, 29.34, 29.22, 28.32, 28.26, 26.72, 24.04, 23.43; HRMS
(FAB) calcd for C40H56N3O7 (M + H) 690.4118, found 690.4142.
1,6,17-Tr is(ben zyloxy)-7,10-d ioxo-6,11,17-tr ia za h ep ta -
d eca n e (17). Meth od A. Trifluoroacetic acid (TFA, 4 mL) was
added to solution of BOC-protected hydroxylamine 12 (0.902
g, 0.94 mmol) in CH2Cl2 (10 mL). The reaction was stirred at
room temperature for 15 min. TFA and CH2Cl2 were removed
under reduced pressure, and saturated NaHCO3 was added
to the oil. This solution was extracted with CHCl3. The organic
layers were combined and washed with brine, dried (MgSO4),
5,16,21-Tr is(b en zyloxy)-4,12,15-t r ioxo-5,11,16-t r ia za -
h en icosa n oic Acid (13). O-Protected hydroxylamine 17 (0.77
g, 1.31 mmol), succinic anhydride (0.20 g, 1.96 mmol), and a
catalytic amount of DMAP were dissolved in pyridine (30 mL).
The solution was heated at 90-95 °C for 2.8 h under argon,
cooled to room temperature, and stirred at room temperature
for 12 h. Pyridine was removed under reduced pressure. The
resulting oil was taken up in ether and extracted with
saturated NaHCO3 and 20% KHCO3. The aqueous layers were
combined and washed with ether. The aqueous layer was then
acidified with 6 N HCl to pH ∼ 3.0 and extracted with CHCl3.
The organic layers were combined, washed with H2O, dried,
and filtered, and the solvents were removed under reduced
pressure. The resulting oil was purified by radial chromatog-
raphy to yield the corresponding acid as a thick oil (0.66 g,
73%). The same reaction conditions were later used to prepare
13 on a 12 g scale, but only confirmatory spectra were obtained
on this preparation: IR (film, cm-1) 3330, 1730, 1655; 1H NMR
(300 MHz, CDCl3) δ 7.42-7.25 (m, 15H), 6.84 (broad s, 1H),
4.84 (s, 2H), 4.82 (s, 2H), 4.48 (s, 2H), 3.76 (t, J ) 5.6, 2H),
3.62 (t, J ) 7.1, 2H), 3.44 (t, J ) 6.5, 2H), 3.23 (q, J ) 5.4,
2H), 2.83 (t, J ) 6.75, 2H), 2.66 (s, 4H), 2.53 (t, J ) 6.90, 2H),
1.70-1.20 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 175.67
(broad), 173.98, 173.74, 172.38, 138.41, 134.33, 134.10, 129.12,
128.83, 128.58, 128.21, 127.48, 127.36, 76.31, 76.02, 72.71,
69.95, 45.39, 44.31, 39.28, 30.60, 29.16, 28.55, 28.28, 28.03,
26.86, 26.48, 26.40, 23.48, 23.22; HRMS (FAB) calcd for
C
39H52N3O8 (M + H) 690.3754, found 690.3732.
28-(ter t-Bu toxycar bon yl)-1,6,17,28-tetr akis(ben zyloxy)-
7,10,18,21-tetr aoxo-6,11,17,22,28-pen taazaoctacosan e (14).
Acid 13 (248 mg, 0.36 mmol) was dissolved in CH3CN (8 mL).
The solution was cooled to 0 °C, triethylamine (110 mL, 0.78
mmol) and DPPA (127 mL, 0.43 mmol) were added, and after
stirring for 10 min, amine 3 (122 mg, 0.40 mmol) was added.
The reaction was stirred at 0 °C for 5 h and then at room
temperature for 3 days. The solvent was removed under
reduced pressure, and the resulting oil was purified by column
chromatography (5% CH3OH/CHCl3) to yield a white solid (349
mg). The product was recrystallized (hexanes-EtOAc) to yield
white crystals (327 mg, 94%): mp ) 63-64.5 °C; IR (film, cm-1
)
3326, 1659; 1H NMR (300 MHz, CDCl3) δ 7.42-7.23 (m, 20H),
6.40-6.24 (m, 2H), 4.85 (s, 2H), 4.84 (s, 2H), 4.81 (s, 2H), 4.47
(s, 2H), 3.68-3.56 (m, 4H), 3.44 (t, J ) 6.4 Hz, 2H), 3.39 (t, J
) 7.0 Hz, 2H), 3.23-3.16 (m, 4H), 2.80 (broad s, 4H), 2.51-
2.45 (m, 4H), 1.22-1.72 (m and s, 27H); 13C NMR (75 MHz,
CDCl3) δ 173.97 (broad), 173.58 (broad), 172.13, 172.03, 156.52,
138.49, 135.54, 134.32, 129.31, 129.11, 128.87, 128.84, 128.65,