Chemistry of Pseudomonic Acid
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2 455
methanol in dichloromethane, 3r was obtained as a white foam
H3), 4.33 (2H, d, J ) 5.7 Hz, CH2), 5.75 (1H, s, 2-H), 6.32 (1H,
t, J ) 5.6 Hz, NH), 7.42 (5H, s, Ar-H); MS (+ve ion FAB,
3-NOBA-Na, m/ z) 516 (MNa+, 43), 494 (MH+, 5), 176 (100).
5-(P h en ylth io)-2-(1-n or m on -2-yl)oxazole (2t). The mona-
mide 3t (198 mg, 0.4 mmol) was cyclized according to the
conditions described in the preparation of 2o to give 2t as a
pale yellow foam (31 mg, 16%); IR (CH2Cl2) 3600, 3550, 3440,
1700, 1580 cm-1; UV (EtOH) λmax 272 nm (ꢀm 16 000); 1H NMR
(CDCl3) δ 0.92 (3H, d, J ) 7.0 Hz, 17-H3), 1.20 (3H, d, J ) 6.3
Hz, 14-H3), 2.24 (3H, s, 15-H3), 2.50 (1H, dd, J ) 2.2, 7.8 Hz,
11-H), 2.79 (1H, dt, J ) 2.2, 5.8 Hz, 10-H), 6.20 (1H, s, 2-H),
7.22-7.30 (5H, m, Ar-H), 7.34 (1H, s, oxazole-H); 13C NMR
(CDCl3) δ 12.7 (C-17), 19.6 (C-15), 20.8 (C-14), 31.6 (C-9), 39.5
(C-8), 42.8 (C-12 and C-4), 55.6 (C-10), 61.3 (C-11), 65.4 (C-
16), 68.9 (C-6), 70.4 (C-7), 71.4 (C-13), 75.1 (C-5), 113.1 (C-2),
127.1 (C-4′), 128.5 (2 × Ar-C), 129.3 (2 × Ar-C), 134.6 (S-C),
135.2 (Ar-C), 140.2 (C-5′), 148.6 (C-3), 165.0 (C-1); MS (EI,
m/ z) 475 (M+, 30), 366, 231 (100); HRMS calcd for C25H33NO6S
475.2029, found 475.2038.
(0.379 g, 40%): IR (CH2Cl2) 3570, 3440, 1770, 1670, 1640 cm-1
UV (EtOH) λmax 219 nm (ꢀm 178 736); 1H NMR (CD3OD) δ 0.94
(3H, d, J ) 7.5 Hz, 17-H3), 1.20 (3H, d, J ) 6.4 Hz, 14-H3),
1.33-1.44 (1H, m, appears as 8 lines, 12-H), 2.18 (3H, d, J )
0.7 Hz, 15-H3), 2.64 (1H, d, J ) 14.4 Hz, 4-H), 2.70 (2H, dd, J
) 2.1, 7.5 Hz, 11-H), 2.80 (1H, dt, J ) 2.1, 5.7 Hz, 10-H), 4.20
(2H, s, CH2NH), 5.85 (1H, s, 2-H), 7.10-7.14 (2H, m, Ar-H),
7.21-7.27 (1H, m, Ar-H), 7.35-7.42 (2H, m, Ar-H); 13C NMR
(CDCl3) δ 12.7 (C-17), 17.0 (C-15), 20.9 (C-14), 21.6 (C-9), 39.6
(C-8), 41.3 (CH2CO), 42.5 (C-4), 42.7 (C-12), 55.6 (C-10), 61.1
(C-11), 65.3 (C-16), 66.8 (C-6), 70.4 (C-7), 71.2 (C-13), 74.9 (C-
5), 119.4 (C-2), 121.3 (2 × Ph), 126.2 (Ph), 129.5 (2 × Ph), 150.4
(O-C), 152.6 (C-3), 167.6 (C-1), 169.2 (CO2Ph); MS (FAB,
3-NOBA-Na, m/ z) 500 (MNa+, 52), 329, 176 (100).
;
5-(P h en yloxy)-2-(1-n or m on -2-yl)oxa zole (2r ). 3r (100
mg, 0.2 mmol) was dissolved in dry THF (6 mL) and treated
with triethylamine (0.16 mL, 1.1 mmol), chlorotrimethylsilane
(0.15 mL, 1.1 mmol), and 4-(dimethylamino)pyridine (few
crystals). The mixture was stirred at room temperature for
1.5 h, filtered, and evaporated under reduced pressure. The
residue was dissolved in acetonitrile (1.2 mL) and treated with
triethylamine (0.1 mL, 0.7 mmol), tetrachloromethane (0.14
mL, 1.45 mmol), and triphenylphosphine (0.18 g, 0.68 mmol).
The reaction mixture was stirred at room temperature for 2.5
h, diluted with ethyl acetate (10 mL), and washed with
NaHCO3 (5 mL) and brine (5 mL). The organic phase was
dried (MgSO4) and evaporated. The residue was dissolved in
THF (3 mL) and water (0.75 mL), treated with 5 M hydro-
chloric acid (2 drops), stirred for 5 min at room temperature,
and then quenched with aqueous NaHCO3. The product was
extracted into ethyl acetate (2 × 7 mL), and the combined
organic extracts were washed with brine (7 mL), dried
(MgSO4), and evaporated to an oil. This was chromatographed
on Kieselgel 60, eluting with 0-6% methanol in dichlo-
romethane, to give 2r as a pale yellow foam (32 mg, 33%): IR
(CH2Cl2) 3600, 3570, 3420, 1630, 1590 cm-1; UV (EtOH) λmax
5-(Eth ylsu lfin yl)-2-(1-n or m on -2-yl)oxa zole (2u ). The
oxazole 2s (130 mg, 0.3 mmol) was dissolved in dichlo-
romethane (10 mL). Saturated aqueous NaHCO3 (5 mL) was
then added, followed by m-chloroperbenzoic acid (75 mg, 0.42
mmol). The reaction mixture was stirred at 0 °C for 20 min
and then diluted with dichloromethane (50 mL). The phases
were separated, and the organic phase was washed with brine
(10 mL), dried (MgSO4), and evaporated. The crude product
was purified by chromatography on Kieselgel 60, eluting with
5% methanol in dichloromethane to give 2u as a white foam
(41 mg, 30%): IR (CH2Cl2) 3550, 3400, 1645 cm-1; UV (EtOH)
λ
max 273.5 (ꢀm 19 315); 1H NMR (CDCl3) δ 0.94 (3H, d, J ) 7.0
Hz, 17-H3), 1.24 (3H, d, J ) 6.3 Hz, 14-H3), 1.30 (3H, t, J )
7.4 Hz, CH2CH3), 2.30 (3H, s, 15-H3), 2.72 (1H, dd, J ) 1.6,
8.0 Hz, 11-H), 2.79 (1H, dt, J ) 2.0, 5.5 Hz, 10-H), 3.23-3.25
[2H, 2 × q, S(O)CH2 (2 isomers)], 6.28 (1H, s, 2-H), 7.58 (1H,
s, oxazole-H); MS (EI, m/ z) 427 (M+, 4), 366 (38), 121 (100);
HRMS calcd for C21H33NO7S 433.1978, found 433.1979.
5-(P h en ylsu lfin yl)-2-(1-n or m on -2-yl)oxa zole (2v). The
oxazole 2t (40 mg, 0.084 mmol) was dissolved in dichlo-
romethane (2 mL) and treated with m-chloroperbenzoic acid
(29 mg of 50-55% pure, 1 equiv) at 0 °C under an argon
atmosphere. After 30 min the reaction mixture was treated
with saturated aqueous NaHCO3 (3 mL), warmed to room
temperature and diluted with dichloromethane (5 mL). The
phases were separated, and the organic phase was washed
with brine (3 mL), dried (MgSO4), and evaporated. The crude
product was chromatographed on Kieselgel 60, eluting with
5% methanol in dichloromethane to give 2v as a pale yellow
1
270 nm (ꢀm 14 694); H NMR (CD3OD) δ 0.95 (3H, d, J ) 7.2
Hz, 17-H3), 1.20 (3H, d, J ) 6.4 Hz, 14-H3), 1.36-1.47 (1H, m,
12-H), 2.15 (3H, s, 15-H3), 2.24 and 2.32 (1H, 2 × d, AB q, J )
9.5 Hz, 4-H), 2.72 (1H, dd, J ) 2.1, 7.6 Hz, 11-H), 2.82 (1H,
dt, J ) 2.2, 5.8 Hz, 10-H), 6.07 (1H, s, 2-H), 6.53 (1H, s, oxazole-
H), 7.10-7.23 (3H, m, Ar-H), 7.37-7.43 (2H, m, Ar-H); MS
(EI, m/ z) 459 (M+, 30), 215 (100); HRMS calcd for C25H33NO7
459.2257, found 459.2246.
N-[[(Eth ylth io)ca r bon yl]m eth yl]m on a m id e (3s). Monic
acid was converted to the isobutoxyformic anhydride on a 5
mmol scale followed by reaction with the trifluoroacetate salt
of glycine ethyl thiolester according to the procedure given
in the general scheme to give 3s as a white foam (1.55 g, 70%);
IR (CHCl3) 3440, 1665, 1640 (sh), 1500 cm-1; UV (EtOH) λmax
foam (13 mg, 31%): IR (CH2Cl2) 3600, 3550, 3440, 1645 cm-1
;
1
UV (EtOH) λmax 279 nm; H NMR (CDCl3) δ 0.94 (3H, d, J )
7.0 Hz, 17-H3), 1.23 (3H, d, J ) 6.2 Hz, 14-H3), 2.17 (3H, s,
15-H3), 2.70 (1H, dd, J ) 2.2, 7.8 Hz, 11-H), 2.77-2.83 (1H,
m, 10-H), 6.18 (1H, s, 2-H), 7.37 and 7.40 [1H, 2 × s, oxazole-H
(2 sulfoxide isomers)], 7.56-7.58 (3H, m, Ar-H), 7.73-7.78 (2H,
m, Ar-H); MS (EI, m/ z) 491 (M+, 7), 474 (30), 456 (40), and
366 (100); HRMS calcd for C25H33NO2S 491.1978, found
491.1975.
1
227 nm (ꢀm 18 866); H NMR (CDCl3) δ 0.95 (3H, d, J ) 6.9
Hz, 17-H3), 1.24 (3H, d, J ) 5.8 Hz, 15-H3), 1.27 (3H, t, J )
7.4 Hz, CH3CH2S), 2.20 (3H, s, 15-H3), 2.74 (1H, dd, J ) 2.1,
7.8 Hz, 11-H), 2.82 (1H, dt, J ) 2.1, 8.9 Hz, 10-H), 2.94 (1H,
q, J ) 7.4 Hz, CH2S), 4.23 (2H, d, CH2NH), 5.78 (1H, s, 2-H),
6.40 (1H, br s, N-H); MS (+ve ion FAB, thioglycerol, m/ z) 446
(MH+, 100).
N-(Car boxym eth yl)m on am ide (10). The isobutoxy mixed
anhydride of monic acid (10 mmol) was converted to 10 on
reaction with glycine under the conditions described in the
general method for preparation of monamides. The addition
of water (10 mL) was required to effect complete solubility.
After a reaction time of 1 h, the mixture was concentrated to
a colorless oil under reduced pressure, dissolved in water, and
applied to a column of HP20SS. Elution with water rapidly
eluted the product as its triethylamine salt. Product-contain-
ing fractions were combined and freeze-dried to a crisp foam
(3.25 g) which was found to be contaminated with 20% monic
acid triethylamine salt. This material was purified as fol-
lows: 1 g of crude product was dissolved in water (10 mL) and
the pH adjusted to 3.0 with 2 M hydrochloric acid. This
solution was applied to a column of HP20SS. Elution with
0-4% THF/water mixtures gave the desired product free from
monic acid contaminant. Product-containing fractions were
combined and freeze-dried to give 10 as a fluffy white solid
(overall yield 35%): IR (KBr) 3409, 1734, 1659, 1630, 1534
5-(Eth ylth io)-2-(1-n or m on -2-yl)oxa zole (2s). The mona-
mide 3s (445 mg, 1 mmol) was cyclized using the procedure
described in the preparation of 2o to give 2s as a yellow oil
(101 mg, 23%): IR (CHCl3) 3530, 3400, 1650 cm-1; UV (EtOH)
1
λmax 277 nm (ꢀm 13 785); H NMR (CDCl3) δ 0.95 (3H, d, J )
6.9 Hz, 17-H3), 1.23 (3H, d, J ) 6.3 Hz, 14-H3), 1.29 (3H, t, J
) 7.4 Hz, CH3CH2), 2.27 (3H, s, 15-H3), 2.77 (2H, q, J ) 7.5
Hz, CH3CH2), 6.21 (1H, s, 2-H), 7.26 (1H, s, oxazole-H); MS
(EI, m/ z) 427 (M+, 8), 183 (62); HRMS calcd for C21H33NO6S
427.2029, found 427.2037.
N-[[(P h en ylth io)car bon yl]m eth yl]m on am ide (3t). Mon-
ic acid was converted to the isobutoxyformic anhydride on a 3
mmol scale followed by reaction with the TFA salt of glycine
phenyl thiolester according to the procedure given in the
general scheme to give 3t as a white foam (0.592 g, 40%): IR
(CH2Cl2) 3550, 3440, 1700, 1665, 1638 cm-1; UV (EtOH) λmax
1
225 nm (ꢀm 21 790); H NMR (CDCl3) δ 0.93 (3H, d, J ) 7.0
Hz, 17-H3), 1.22 (3H, d, J ) 6.2 Hz, 14-H3), 2.21 (3H, s, 15-