Stereocontrolled synthesis of tricyclic fused oxazolidinone as antibacterial agent

Article abstract of DOI:10.1002/jhet.5570430438

Tricyclic fused oxazolidinone 3a and 3b have been synthesized as antibacterial agents in 12 and 11 steps respectively. The key intermediates 10a and 10b have been developed via opening of epoxide 9a and 9b and cyclization by the resulting oxygen anion att

Full text of DOI:10.1002/jhet.5570430438

Jul-Aug 2006
1071
Stereocontrolled Synthesis of Tricyclic Fused Oxazolidinone
as Antibacterial Agent
Yingjie Cui,* Yaxian Dang, Yushe Yang* and Ruyun Ji
Shanghai Institute of Materia Medica, Shanghai Institute for Biological Science,
Chinese Academy of Sciences, Shanghai 201203, China.
E-mail address: cuiyingjie@yahoo.com
Received August 12, 2005
O
O
N
O
Br
N
O
NHAc
NHAc
O
O
3a
3b
Tricyclic fused oxazolidinone 3a and 3b have been synthesized as antibacterial agents in 12 and 11 steps
respectively. The key intermediates 10a and 10b have been developed via opening of epoxide 9a and 9b
and cyclization by the resulting oxygen anion attack.
J. Heterocyclic Chem., 43, 1071 (2006).
Introduction.
O
O
Oxazolidinones, a promising new class of synthetic
antibacterial agents, exhibit excellent antibacterial
activity against multi-drug resistant Gram-positive
organisms [1,2]. Linezolid (zyvoxR, 1), the only
oxazolidinone approved by the FDA, has already taken
its place in the clinic for treatment of Gram-positive
infections [3,4]. They have a novel mechanism of
action that is shown to selectively and uniquely bind to
the 50S ribosomal subunit, inhibiting bacterial
translation at the initiation phase of protein synthesis.
It appears that there is a lack of cross-resistance with
any known antibiotics [5,6]. Many efforts are focused
on oxazolidinone with potent activity and broad
spectrum [7,8]. Researchers at Pharmacia corporation
have synthesized tricyclic fused oxazolidinone 2; it
shows comparable antibacterial activity to Linezolid
[9-11]. In the period of our research on oxazolidinone,
we hope to investigate antibacterial activity of
restricted conformation oxazolidinones. According to
the structure of compound 2 and principle of isosters
in medicinal chemistry, we have designed that the
methylene group of compound 2 has been replaced by
the heteroatom oxygen; in addition, the five-membered
ring was enlarged to a six-membered ring. Thus the
new tricyclic fused oxazolidinones 3a and 3b were
prepared to investigate structure-activity relationship.
N
O
Br
N
O
NHAc
NHAc
O
O
3a
3b
Results and Discussion.
The synthetic route is outlined in Scheme ꢀ on the base
of reference [12]. Phenol 4 was condensated with (Z)-1-
acetoxy-4-chloro-2-butene which was prepared from (Z)-
2-butene-1,4-diol in two steps of acylation and chlorinate
to give ether 5. Ether 5 was then hydrolyzed, hydrogenated
and protected with CBZ to yield alcohol 7. Alcohol 7 was
converted into epoxide 8 by the Sharpless asymmetric
epoxidation with high enantiomeric excess (%ee > 99%,
confirmed by HPLC analysis) [13]. Racemic epoxide 8
was prepared by m-CPBA oxidation of alcohol 7. Epoxide
8 was protected with TBDMSCl to afford compound 9.
Compound 9 was treated with 1.6 M n-BuLi-cyclohexane
at –78°C to afford tricyclic fused oxazolidinone 10.
Functional group manipulation of oxazolidinone 10
yielded the desired acetamide derivatives 3a and 3b. When
compound 13b was hydrogenated, loss of bromo gave rise
to 14. So thioacetic acid was used to reduce and acylate of
azide 13b to afford 3b.
Antibacterial activity of Compounds 3a and 3b was
tested in vitro against a panel of clinical isolates of Gram-
positive species. Minimum inhibitory concentration
(MIC) values were determined using Agar dilution
methodology [14]. Linezolid was selected as reference
compound. Compounds 3a and 3b exhibit weak
antibacterial activity. Comparing with compound 2, the
O
O
F
O
N
N
O
N
O
NHAc
NHAc
1
2

1072
Y. Cui, Y. Dang, Y. Yang and R. Ji
Vol 43
Scheme 1
a
b
OCOEt
X
NO2
O
X
X
NO2
OH
Cl
+
OCOEt
5a X=H
4a X=H
4b X=Br
5b X=Br
c,d
f
e
NO2
X
NHCBZ
X
NHCBZ
O
OH
O
OH
O
OH
O
6a X=H
6b X=Br
7a X=H
8a X=H
8b X=Br
7b X=Br
O
N
O
O
g
h
i
X
X
N
O
X
X
NHCBZ
O
OTBS
OH
OTBS
O
O
9a X=H
9b X=Br
O
O
11a X=H
11b X=Br
10a X=H
10b X=Br
O
O
j
k
N
O
X
N
O
Br
N
O
OSO2CH3
N3
NHAc
O
O
O
12a X=H
12b X=Br
13a X=H
13b X=Br
3b
l
O
O
m
N
O
N
O
NH2
NHAc
O
O
3a
14
Reagents and conditions: (a) Acetone, K2CO3, reflux; (b) 10% KOH; c. SnCl2.2H2O, EtOH; (d) CBZ-Cl, NaHCO3, acetone:H2O = 2:1;
(e) L-(+)DET, TBHP, Ti(Oi-Pr)4, 4Å; (f) TBDMSCl, imidazole, DMAP, dry DMF; (g) n-BuLi, dry THF, -78 °C to rt; (h) (n-Bu)4NF, dry THF; (i)
MsCl, Et3N, CH2Cl2; (j) NaN3, DMF, 70-80 °C; (k) CH3COSH, rt; (l) 10% Pd/C, CH3OH; (m) (Ac)2O, Py, 0 °C.
in anhydrous acetone (100 mL) was heated to reflux overnight
with stirring. After concentration in vacuo, the residue was
poured into H2O. The aqueous phase was extracted with AcOEt,
dried over Na2SO4, then concentrated in vacuo. The residue was
purified by silica gel column chromatography (petroleum–
AcOEt = 2:1) to give 5a and 5b in 70 and 67% yield,
respectively.
ring of compounds 3a and 3b is enlarged and ethylene is
replaced by oxygen, however, antibacterial activity of
them is poor. We suspect that restricted conformation
between aryl and oxazolidinone ring in the new
oxazolidinone derivatives is not favorable for receptor.
EXPERIMENTAL
(2Z)-4-(2-nitrophenoxy) but-2-enyl propionate (5a).
This compound was obtained as yellow oil. 1H nmr
(deuteriochloroform): ꢀ 7.80(m, 1H), 7.45-7.50(m, 1H), 7.05(m,
1H), 7.00(m, 1H), 5.82-5.80(m, 1H), 5.70-5.80(m, 1H), 4.80(m,
2H), 4.70(m, 2H), 2.35(q, J= 7.7Hz, 2H), 1.10(t, J= 7.7Hz,1H;
ms: m/z 265(M+).
Melting points were determined on a MEL-TEMP melting
point apparatus and were uncorrected. 1H NMR spectral data were
recorded using a Bruker AM-400 spectrometer. Chemical shifts
are reported in ꢀ units (ppm). Coupling contants (J) are reported in
hertz (Hz). Mass spectra are recorded on a MAT-711. Elemental
analysis was recorded on an Elemental vario 1106. Optical
rotations were measured with a PERKIN-ELMER 241.
(2Z)-4-(5-bromo-2-nitrophenoxy)but-2-enyl propionate (5b).
This compound was obtained as yellow oil. 1H nmr
(deuteriochloroform): ꢀ 7.98(d, J=9.0 Hz, 1H), 7.20(d, J=2.7 Hz,
1H), 6.90(dd, J=9.0 Hz, J=2.7 Hz, 1H), 5.78-5.85(m, 2H),
4.73(m, 2H), 4.67(m, 2H), 2.35(t, J=7.6 Hz, 2H), 1.80(t, J=17.6
Hz, 3H).
General Procedure for the Synthesis of Compounds (5a) and (5b).
A mixture of 4 (84.0 mmol), (Z)-1-acetoxy-4-chloro-2-butene
(11.7 g, 84.0 mmol) and anhydrous K2CO3 (12.2 g, 88.0 mmol)

Jul-Aug 2006
Stereocontrolled Synthesis of Tricyclic Fused Oxazolidinone as Antibacterial Agent
1073
Anal. Calcd. for C18H18BrNO4: C, 55.10; H, 4.59; N, 3.57.
Found: C, 55.25; H, 4.54; N, 3.31.
General Procedure for the Synthesis of Compounds (6a) and
(6b).
General Procedure for the Synthesis of Compounds (8a) and
(8b).
To a stirred solution of 5 (59.1 mmol) in CH3OH (50 mL)
was added dropwise10% KOH in CH3OH at rt. The mixture was
stirred overnight. The reaction mixture was poured into H2O.
The aqueous phase was extracted with AcOEt, dried over
Na2SO4, then concentrated in vacuo. The residue was purified by
silica gel column chromatography (petroleum– acetone = 2:1) to
give 6a and 6b in 55 and 73% yield, respectively.
4Å Molecular sieves (1.2 g) was suspended in anhydrous
CH2Cl2 (50 mL) at –40 to -20 °C. To the cooled mixture was
added a solution of L-(+)DET (1.71 g, 8.3 mmol) in anhydrous
CH2Cl2 (5 mL), a solution of Ti(Oi-Pr)4 (1.9 g, 7.0 mmol) in
anhydrous CH2Cl2 (5 mL) and TBHP (3.6 mL, 4.949 M, 18.0
mmol). After stirring for 1h at –40 to -20 °C, a solution of
compound 7 (7.3 mmol) in anhydrous CH2Cl2 (12 mL) was
added dropwise, and the reaction mixture was stirred for 20h at
–40 to -20 °C. To cooled (0 °C) reaction mixture was added
10% L-Tartaric acid (20 mL). After stirring for 1h, the mixture
was diluted with brine (60 mL) and extracted with AcOEt, dried
over Na2SO4, then concentrated in vacuo. The residue was
redissolved in Et2O. To the cooled (0 °C) solution was added 1
N NaOH (20 mL). After stirring for 1h, the mixture was diluted
with brine (60 mL) and extracted with AcOEt, dried over
Na2SO4, then concentrated in vacuo. The residue was purified by
silica gel column chromatography (petroleum– acetone = 3:2)
followed by recrystallization from Et2O to give 8a and 8b in 67
and 53% yield, respectively.
(2Z)-4-(2-Nitrophenoxy)but-2-en-1-ol (6a).
1
This compound was obtained as red oil. H nmr (deuterio-
chloroform): ꢀ 7.80(m, 1H), 7.45(m, 1H), 7.05(m, 1H), 7.00(m,
1H), 5.85-5.95(m, 1H), 5.75-5.82(m, 1H), 4.78(m, 2H), 4.28(m,
2H); ms: m/z 209(M+).
(2Z)-4-(5-Bromo-2-nitrophenoxy)but-2-en-1-ol (6b).
This compound was obtained as yellow solid, mp 80-82°C; 1H
nmr (deuteriochloroform): ꢀ 7.75(d, J=8.5 Hz, 1H), 7.38(dd,
J=8.5 Hz, J=2.8 Hz, 1H), 5.58-6.00(m, 1H), 5.60-5.75(m, 1H),
4.56(m, 2H), 4.35(m, 2H), 1.64(brs, 2H);ms: m/z 287,289(M+).
Anal. Calcd. for C10H10BrNO4: C, 41.67; H, 3.47; N, 4.86.
Found: C, 42.30; H, 3.53; N, 4.60.
Benzyl 2-(((2R,3S)-3-(hydroxymethyl)oxiran-2-yl)methoxy)-
phenylcarbamate (8a).
General Procedure for the Synthesis of Compounds (7a) and
(7b).
This compound was obtained as white solid, mp 57-60°C;
A mixture of 6 (32.0 mmol) and SnCl2 .2 H2O (36.86 g, 163
mmol) in absolute C2H5OH (80 mL) was heated at 80-90°C for 2
h with stirring. The reaction mixture was poured into ice-H2O,
the aqueous phase was adjusted to pH 7-8 by NaOH and
saturated NaHCO3, the resulting mixture was filtered and the
filtrate was extracted with AcOEt, dried over Na2SO4. The
solution was concentrated in vacuo to give the amine as red oil,
which was used for the next reaction without further
purification.
The crude amine was dissolved in acetone (60 mL) and H2O
(30 mL). To the cooled solution was added NaHCO3 (4.164 g,
50 mmol) and then benzyl chloroformate (5.79 g, 90% W/W,
30.6 mmol) over 10 min via syringe. The mixture was warmed
to rt and stirred overnight. After concentration in vacuo, the
residue was extracted with AcOEt, dried over Na2SO4, then
concentrated in vacuo. The residue was purified by silica gel
column chromatography (petroleum– AcOEt = 2:1) to give 7a
and 7b in 70 and 18% yield, respectively.
20
[ꢁ]D = +0.15 (c 0.52, DMSO); %ee > 99%; 1H nmr
(deuteriochloroform): ꢀ 8.12 (brs, 1H), 7.30-7.43(m, 6H), 6.95-
7.00(m, 2H), 6.85(m, 1H), 5.20(s, 2H), 4.26(dd, J=11.1 Hz,
J=4.4 Hz, 1H), 4.20(dd, J=11.2 Hz, J=6.4 Hz, 1H), 3.90(dd,
J=12.5 Hz, J=4.4 Hz, 1H), 3.82(dd, J=12.5 Hz, J=5.5 Hz, 1H),
3.43-3.51(m, 1H), 3.30-3.33(m, 1H), 1.90(brs, 1H); ms: m/z
329(M+). ꢀ
Anal. Calcd for C18H19NO5: C, 65.65; H, 5.78; N, 4.26. Found:
C, 65.41; H, 5.94; N, 4.59.
Benzyl 4-bromo-2-(((2R,3S)-3-(hydroxymethyl)oxiran-2-yl)-
methoxy)phenylcarbamate (8b).
This compound was obtained as white solid, mp 92-94 °C;
20
[ꢁ]D
=
-6.02 (c 0.42, DMSO); %ee > 99%;ꢀ 1H nmr
(deuteriochloroform):
ꢀ 8.02(brs, 1H), 7.32-7.44(m, 5H),
7.12(dd, J=8.6 Hz, J=2.0 Hz, 1H), 6.99(d, J=2.0 Hz, 2H), 5.20(s,
2H),4.58(dd, J=11.3 Hz, J=3.6 Hz, 1H), 4.38(dd, J=11.3 Hz,
J=6.6 Hz, 1H), 3.93(dd, J=12.4 Hz, J=4.4 Hz, 1H), 3.85(dd,
J=12.5 Hz, J=5.4 Hz, 1H), 3.42-3.47(m, 1H), 3.30-3.35(m, 1H);
ms: m/z 407, 409(M+).
Benzyl 2-(((2Z)-4-hydroxybut-2-enyl)oxy)phenylcarbamate
(7a).
Anal. Calcd for C18H18BrNO5: C, 52.94; H, 4.41; N, 3.43.
Found: C, 52.67; H, 4.48; N, 3.21.
This compound was obtained as orange oil. 1H nmr
(deuteriochloroform): ꢀ 8.12 (brs, 1H), 7.30-7.50(m, 6H), 6.95-
7.00(m, 2H), 6.85(m, 1H), 5.75-5.85(m, 2H), 5.19(s, 2H), 4.60-
4.65(m, 2H), 4.50-4.55(m, 2H); ms: m/z 313(M+).
General Procedure for the Synthesis of Compounds (9a) and
(9b).
To the cooled (0°C) solution of TBDMSCl (0.362 g, 2.41
mmol), imidazole (0.169 g, 2.49 mmol) and a catalytical
amount of DMAP in anhydrous DMF (2 mL) was added a
solution of compound 8 (1.57 mmol) in anhydrous DMF (2 mL).
The reaction mixture was allowed to warm to rt and stirred
overnight. The mixture was poured into ice-H2O and extracted
with CH2Cl2, dried over Na2SO4, then concentrated in vacuo.
The residue was purified by silica gel column chromatography
Benzyl 4-bromo-2-(((2Z)-4-hydroxybut-2-enyl)oxy)phenyl-
carbamate (7b).
This compound was obtained as yellow solid, mp 66-70 °C;
1H nmr (deuteriochloroform): ꢀ 8.00(brs, 1H), 7.28-7.44(m, 8H),
7.09(dd, J=8.5 Hz, J=1.9 Hz, 1H), 7.09(d, J=1.9 Hz, 1H), 5.84-
5.96(m, 1H),5.74-5.82(m, 1H), 5.19(s, 2H), 4.70(m, 1H),
4.63(m, 2H),4.26(m, 2H), 1.83(brs, 2H);ms: m/z 391,393(M+).

1074
Y. Cui, Y. Dang, Y. Yang and R. Ji
Vol 43
(petroleum– acetone = 10:1) to give 9a and 9b in 74 and 58%
yield, respectively.
(3R,3aS)-3-(hydroxymethyl)-3a,4-dihydro-3H-[1,3]oxazolo[4,3-c]-
[1,4]benzoxazin-1-one (11a).
Benzyl 2-(((2R,3S)-3-((1,1-dimethylethyl)dimethylsilanemethyl)-
oxiran-2-yl)methoxy)phenylcarbamate (9a).
This compound was obtained as white solid, mp 116-117°C;
20
1
[ꢁ]D = -45.04 (c 1.0, DMSO); H nmr (deuteriochloroform): ꢀ
7.98(m, 1H), 6.93-7.06(m, 3H), 4.48(dd, J=10.5 Hz, J=3.1 Hz,
1H), 4.34-4.38(m, 1H), 4.16-4.22(m, 1H), 4.02(dd, J=12.5 Hz,
J=3.8 Hz, 1H), 3.94(t, J=10.4 Hz, 1H), 3.85(dd, J=12.6 Hz,
J=4.0 Hz, 1H), 2.29(brs, 1H); ms: m/z 221(M+).
This compound was obtained as colorless oil. 1H nmr
(deuteriochloroform): ꢀ 8.12(brs, 1H), 7.30-7.43(m, 4H),6.95-
7.00(m, 2H),6.85(m, 1H),5.22(s, 2H), 4.30(dd, J=11.4 Hz, J=3.7
Hz, 1H), 4.10(dd, J=11.4 Hz, J=6.9 Hz, 1H), 3.85(q, 2H),
3.40(q, 1H), 3.25(t, J=4.8 Hz, 1H), 0.90(s, 9H), 0.10(s, 3H).
Anal. Calcd. for C11H11NO4: C, 59.73; H, 4.98; N, 6.33.
Found: C, 59.61; H, 5.02; N, 6.00.
Benzyl 4-bromo-2-(((2R,3S)-3-((1,1-dimethylethyl)dimethyl-
silanemethyl)oxiran-2-yl)methoxy)phenylcarbamate (9b).
This compound was obtained as yellow oil. 1H nmr
(2R,3aS)-7-Bromo-3-(hydroxymethyl)-3a,4-dihydro-3H-[1,3]-
oxazolo[4,3-c][1,4]benzoxazin-1-one (11b).
This compound was obtained as white solid, mp 130-132°C;
(deuteriochloroform):
ꢀ 8.05(brs, 1H), 7.34-7.44(m, 5H),
20
[ꢁ]D = -24.1 (c 0.22, DMSO); 1H nmr (deuteriochlooform): ꢀ
7.25(brs, 1H), 7.11(dd, J=8.7 Hz, J=2.1 Hz, 1H), 6.98(d, J=2.1
Hz, 1H), 5.20(s, 2H), 4.30(dd, J=11.3 Hz, J=3.2 Hz, 1H), 4.08(q,
1H), 3.75(q, 2H), 3.38(m, 1H), 3.25(m, 1H), 0.92(s, 9H), 0.10(s,
3H).
7.98(dꢀt, 1H), 7.10-7.12(m, 2H),4.49(dd, J=10.6 Hz, J=3.1 Hz,
1H),4.35-4.39(m, 1H), 4.14-4.20(m, 1H), 4.03(dd, J=12.4 Hz,
J=3.8 Hz, 1H), 3.83-3.94(m, 2H), 2.05(brs, 2H); ms: m/z 299,
301(M+).
Anal. Calcd. for C11H10BrNO4: C, 44.00; H, 3.33; N, 4.67.
Found: C, 43.97; H, 3.31; N, 4.39.
General Procedure for the Synthesis of Compounds (10a) and (10b).
To a solution of compound 9 (4.0 mmol) in dry THF (30 mL)
at -78 °C under Ar was added dropwise (4.0 mL 1.27 M n-
butylithium-cyclohexane, 5.0 mmol). After stirring for 2h at –78
°C, the reaction mixture was allowed to warm to rt and
overnight. To the cooled (0 °C) solution was added saturated
NH4Cl (20 mL) and extracted with AcOEt, dried over Na2SO4,
then concentrated in vacuo. The residue was purified by silica
gel column chromatography (petroleum– acetone = 3:1) to give
10a and 10b in 76 and 89% yield, respectively.
General Procedure for the Synthesis of Compounds (12a) and
(12b).
To the cooled (0°C) solution of compound 11 (1.86 mmol)
and Et3N (0.6 mL, 4.33 mmol) in CH2Cl2 (25 mL) was added
dropwise MeSO2Cl with stirring, the reaction mixture was
allowed to warm to rt and stirred overnight. The mixture was
diluted with H2O and extracted with CH2Cl2, dried over Na2SO4,
then concentrated in vacuo. The residue was purified by silica
gel column chromatography (CH2Cl2– CH3OH = 25:1) followed
by recrystallization from Et2O to give 12a and 12b in 97 and
94% yield, respectively.
(3R,3aS)-3-((1,1-Dimethylethyl)dimethylsilanemethyl)-3a,4-
dihydro-3H-[1,3]oxazolo[4,3-c][1,4]benzoxazin-1-one (10a).
This compound was obtained as white solid, mp 123-125 °C;
20
1
[ꢁ]D = -62.02 (c 1.0, DMSO); H nmr (deuteriochloroform): ꢀ
8.00(m, 1H), 6.95-7.05(m, 3H), 4.45(2ꢀdd, J=10.6 Hz, J=3.2
Hz, 1H), 4.25-4.30(m, 1H), 4.09-4.15(m, 1H), 3.87-3.96(m, 3H),
0.90(s, 9H), 0.10(s, 3H); ms: m/z 335(M+).
((3R,3aS)-1-Oxo-3a,4-dihydro-3H-[1,3]oxazolo[4,3-c][1,4]benz-
oxazin-3-yl)methyl methanesulfonate (12a).
This compound was obtained as white solid, mp 124-126 °C;
[ꢁ]D20 = -61.39 (c 0.54, DMSO); 1H nmr (deuteriochloroform): ꢀ
7.98(m, 1H), 6.95-7.09(m, 3H), 4.48-4.56(m, 4H), 4.12-4.16(m,
1H), 3.94(t, J=10.3 Hz, 1H), 3.18(s, 3H); ms: m/z 299(M+).
Anal. Calcd. for C12H13NO6S: C, 48.16; H, 4.35; N, 4.68.
Found: C, 48.21; H, 4.41; N, 4.86.ꢀ
Anal. Calcd. for C17H26NO4Si: C, 60.90; H, 7.46; N, 4.18.
Found: C, 61.12; H, 7.37; N, 4.06.
(3R,3aS)-7-Bromo-3-((1,1-dimethylethyl)dimethylsilanemethyl)-
3a,4-dihydro-3H-[1,3]oxazolo[4,3-c][1,4]benzoxazin-1-one (10b).
This compound was obtained as white solid; mp 130-132°C;
[ꢁ]D20 = -45.2 (c 0.025, DMSO); 1H nmr (deuteriochloroform): ꢀ
7.88(dd, J=6.0 Hz, J=3.1 Hz, 1H), 7.10-7.13(m, 2H),4.45(dd,
J=10.4 Hz, J=3.3 Hz, 1H), 4.26-4.30(m, 1H), 4.07-4.12(m, 1H),
3.86-3.96(m, 3H), 0.90(s, 9H), 0.10(s, 3H); ms: m/z
413,415(M+). ꢀ
((3R,3aS)-7-Bromo-1-oxo-3a,4-dihydro-3H-[1,3]oxazolo[4,3-c]-
[1,4]benzoxazin-3-yl)methyl methanesulfonate (12b).
This compound was obtained as white solid, mp 117-118 °C;
20
1
[ꢁ]D = -18.0(c 0.30, DMSO); H nmr (deuteriochloroform): ꢀ
7.85(m, 1H), 7.12(m, 2H), 4.48-4.55(m, 4H), 4.07-4.12(m, 1H),
3.95(t, J=10.3 Hz, 1H), 3.12(s, 3H); ms: m/z 377, 379(M+).
Anal. Calcd. for C12H12BrNO6S: C, 38.10; H, 3.17; N, 3.70.
Found: C, 38.53; H, 3.00; N 3.56.
Anal. Calcd. forꢀ C17H26NO4Si: C, 49.28; H, 5.80; N, 3.38.
Found: C, 49.27; H, 5.65; N, 3.08.
General Procedure for the Synthesis of Compounds (11a) and
(11b).
General Procedure for the Synthesis of Compounds (13a) and
(13b).
To the cooled (0 °C) solution of compound 10 (3.0 mmol) in
THF (15 mL) was added a solution of n- Bu4NF. After stirring
for 2h, the reaction mixture was diluted with H2O and extracted
with AcOEt, dried over Na2SO4, then concentrated in vacuo. The
residue was purified by silica gel column chromatography
(CH2Cl2– CH3OH = 25:1) to give 11a and 11b in 62 and 88%
yield, respectively.
A mixture of compound 12 (1.0 mmol) and NaN3 (0.265 g,
4.0 mmol) in DMF (10 mL) was heated at 70-80 °C overnight
with stirring. The mixture was diluted with H2O and extracted
with AcOEt, dried over Na2SO4, then concentrated in vacuo to
give 13a and 13b respectively.

Jul-Aug 2006
Stereocontrolled Synthesis of Tricyclic Fused Oxazolidinone as Antibacterial Agent
1075
Anal. Calcd. for C13H14N2O4.1/4C4H8O: C, 58.53; H, 5.44; N,
10.51. Found: C, 58.92; H, 5.63; N, 10.43.
(3S,3aS)-3-(Azidomethyl)-3a,4-dihydro-3H-[1,3]oxazolo[4,3-c]-
[1,4]benzoxazin-1-one (13a).
This compound was obtained as yellow oil , which was used
for the next reaction without further purification.
N-(((3S,3aS)-7-bromo-1-oxo-3a,4-dihydro-3H-[1,3]oxazolo[4,3-
c][1,4]benzoxazin-3-yl)methyl) acetamide (3b).
The solution of compound 13b (0.19 g, 0.58 mmol) in
CH3COSH (10 mL) was stirred at rt overnight. The mixture was
diluted with AcOEt (20 mL), the organic layer was washed with
saturated Na2CO3, H2O and brine respectively then dried over
Na2SO4 The resulting solution was then concentrated in vacuo.
The residue was purified by silica gel column chromatography
(CH2Cl2– CH3OH = 25:1) to give 3b 0.14 g (70.2%) as white
solid, mp 184-186 °C; [ꢀ]D = -3.81 (c 0.535, DMSO); H nmr
(deuteriochloroform): ꢁ 8.28(t, J=5.5 Hz, 1H), 7.82(d, J=8.8 Hz,
3H), 7.18-7.22(m, 2H), 4.54(dd, J=10.0 Hz, J=2.7 Hz, 1H), 4.45-
4.50(m, 1H), 4.04(t, J=10.0 Hz, 1H), 3.94-4.00(m, 1H), 3.46-
3.58(m, 2H),1.86(s, 3H); ms: m/z 340, 342(M+).
(3S,3aS)-3-(azidomethyl)-7-bromo-3a,4-dihydro-3H-[1,3]oxazolo-
[4,3-c][1,4]benzoxazin-1-one (13b).
This compound was obtained 0.191 g (44%) as white solid,
20
1
mp 116-117 °C; [ꢀ]D = -48.67 (c 0.285, DMSO); H nmr
(deuteriochloroform): ꢁ 7.85(m, 1H), 7.12(m, 2H), 4.49(dd,
J=10.6 Hz, J=3.2 Hz, 1H), 4.36-4.41(m, 1H),4.01-4.06(m, 1H),
3.95(t, J=10.3 Hz, 1H), 3.76(dd, J=13.0 Hz, J=5.4 Hz, 1H),
3.76(dd, J=13.0 Hz, J=5.4 Hz, 1H); ms: m/z 324, 326(M+).
Anal. Calcd. for C11H9BrN4O3.1/4C4H8O2: C, 41.50; H,3.17;
N, 16.14. Found: C, 41.50; H, 2.80; N, 16.48.
20
1
(3S,3aS)-3-(aminomethyl)-3a,4-dihydro-3H-[1,3]oxazolo[4,3-c]-
[1,4]benzoxazin-1-one (14).
Anal. Calcd. for C13H13BrN2O4.1/4C4H8O2: C, 46.28; H, 4.13;
N 7.71. Found: C, 46.53; H, 3.70; N, 7.85.
A mixture of compound 13a and 10% Pd/C (0.027 g, 4.0
mmol) in CH3OH (10 mL) was stirred for 7h at rt under a H2
atmosphere (1 atm). The resulting mixture was filtered and
concentrated in vacuo, the residue was purified by silica gel
column chromatography (CH2Cl2– CH3OH = 10:1) followed by
recrystallization from Et2O to give 14 0.200 g (97%) as white
REFEFRENCES
[1] S. Brickner, D. Hutchinson, M. Barbachyn, P. Manninen, D.
Ulanowicz, S. Garmon, K. Grega, S. Hedges, D. Toops, C. Ford and G.
Zurenko, J. Med. Chem. 39, 673 (1996).
[2] D. J. Diekema and R. N. Jones, Drugs, 59, 7 (2000).
[3] Scrip, 2484, 24 (1999).
[4] B. Bozdogan and P. C. Appelbaum, Int. J. Antimicrob.
Agents, 23, 113 (2004).
20
solid, mp 88-90°C; [ꢀ]D = -62.39 (c 1.0, DMSO); 1H nmr
(deuteriochloroform): ꢁ 8.00(m, 1H), 6.92-7.06(m, 3H), 4.48(dd,
J=10.5 Hz, J=3.1 Hz, 1H), 4.26-4.31(m, 1H), 4.03-4.09(m, 1H),
3.92(t, J=10.4 Hz, 1H), 3.16(dd, J=13.6 Hz, J=4.6 Hz, 1H),
3.09(dd, J=13.6 Hz, J=5.5 Hz, 1H), 1.48(brs, 2H); ms: m/z
220(M+).
[5] S. M. Swaney, H. Aoki and M. C. Ganoza, Antimicrob.
Agents Chemother., 41, 2132 (1997).
[6] D. Clemett and A. Markham, Drugs, 59, 815 (2000).
Anal. Calcd. for C11H12N2O3: C, 60.00; H, 5.45; N, 12.73.
Found: C, 59.97; H, 5.55; N, 12.84.
[7]
[8] B. Ryan, H.T. Ho, P. Wu, Exp. Opin. Invest. Drugs, 9, 2945
(2000).
N. Woodford, Exp. Opin. Invest. Drugs, 12, 117 (2003).
N-(((3S,3aS)-1-oxo-3a,4-dihydro-3H-[1,3]oxazolo[4,3-c][1,4]-
benzoxazin-3-yl)methyl) acetamide (3a).
[9] S. J. Brickner, US Patent 5,231,188 (1993); Chem. Abstr.,
120, 1833005u (1994).
To the cooled (0 °C) solution of compound 14 (0.200 g, 0.91
mmol) and pyridine (0.4 mL, 2.5 mmol) in CH2Cl2 (15 mL) was
added (Ac)2O with stirring, the reaction mixture was allowed to
warm to rt and overnight. The mixture was washed with H2O
and brine respectively, then dried over Na2SO4, then
concentrated in vacuo. The residue was purified by silica gel
column chromatography (CH2Cl2– CH3OH = 20:1) to give 3a
[10] S. J.Brickner, US Patent 5,247,090 (1993); Chem. Abstr.,
120, 2103760w (1994).
[11] D. M. Gleave, S. J. Brickner, P. R. Manninen, D.A. Allwine,
K. D. Lovasz, D. C. Rohrer, J. A. Tucker, G. E. Zurenko and C. W.
Ford, Bioorg. Med. Chem. Lett., 8, 1231 (1998).
[12] D. M. Gleave, S. J. Brickner, J. Org. Chem., 61, 6470
(1996).
[13] HPLC analysis was performed using the following
conditions: Chiralcel OD (Daicel) (0.46cm ꢀ 25cm), mobile phase: n-
hexane/isopropanol = 9:1, flow rate 0.4 mL/min, temperature: 25 °C.
[14] National Committee for Clinical Laboratory Standards.
NCCLS Document M7-A3 (ISBN 1-56238-209-8); NCCLs: 771
Lancaster Ave., Villanova, PA 19085, 1993.
20
0.15 g (63%) as white solid, mp 136-138°C; [ꢀ]D = -38.45 (c
0.75, DMSO); 1H nmr (deuteriochloroform): ꢁ 7.96(m, 1H),
6.93-7.06(m, 3H), 6.33(brs, 1H), 4.53(dd, J=9.9 Hz, J=2.5 Hz,
1H), 4.38-4.44(m, 1H), 3.93-4.00(m, 1H), 3.89(t, J=10.2 Hz,
1H), 3.65-3.77(m, 2H),2.05(s, 3H); ms: m/z 262(M+).