3430 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 21
Buynak et al.
(1H, d, J ) 1.18 Hz), 7.07 (1H, s), 5.50 (1H, d, J ) 1.23 Hz),
5.00 (1H, d, A of AB q, J ) 13 Hz), 4.75 (1H, d, B of AB q, J
) 13 Hz), 3.65 (1H, d, A of AB q, J ) 18 Hz), 3.41 (1H, d, B of
AB q, J ) 18 Hz), 2.04 (3H, s); 13C NMR (CDCl3) δ 170.3 (s),
161.0 (s), 160.2 (s), 139.3 (s), 139.1 (s), 135.8(s), 132.4 (d), 130.5,
129.7, 129.0, 128.3, 128.1, 127.9, 127.7, 127.0, 121.7(s), 79.7
(d), 63.1 (t), 57.7 (d), 28.0 (t), 20.5 (q); high-resolution mass
spectrum for [C30H25NO5SNa]+, i.e. [M + Na]+, m/ z calcd
534.1351, found 534.1352. Anal. (C30H25NO5S) C, H, N.
Ben zh yd r yl 7-[(Z)-Ben zylid en e]cep h a losp or a n a te Su l-
fon e (10). This compound was prepared from the sulfide 9
(0.68 g, 1.3 mmol) as described for 5 to give a white solid (yield
) 57%, 0.410 g): Rf ) 0.40 in CH2Cl2; mp 61-63 °C; IR (CHCl3)
dried (Na2SO4), concentrated, and purified by column chro-
matography (CH2Cl2) to give a white solid (0.86 g, 83% yield).
Rf ) 0.41 in CH2Cl2; mp 48-50 °C; IR (CHCl3) 3025, 1780,
1730 cm-1; 1H NMR (CDCl3) δ 7.32 (10H, m), 6.96 (1H, s), 6.44
(1H, s), 5.05 (1H, s) 4.92 (1H, d, A of AB q, J ) 13 Hz), 4.67
(1H, d, B of AB q, J ) 13 Hz), 3.46 (1H, d, A of AB q, J ) 18
Hz), 3.26 (1H, d, B of AB q, J ) 18 Hz), 1.96 (3H, s); 13C NMR
(CDCl3) δ 170.15 (s), 160.60 (s), 157.04 (s), 141.77 (s), 139.05
(s), 138.86 (s), 128.32, 127.97, 127.89, 127.49, 126.92, 123.30
(s), 107.94 (d), 79.82 (d), 62.90 (t), 58.02 (d), 27.68 (t), 20.42
(q). Anal. (C24H20BrNO5S) C, H, N.
Ben zh yd r yl 7-[(E)-Br om om eth ylen e]cep h a losp or a n -
a te Su lfon e (16). This compound was prepared from the
corresponding sulfide 13 as described above for 5 to give a
white solid (yield ) 71%): Rf ) 0.43 in 2% EtOAC in CH2Cl2;
1
3025, 2925, 1780, 1730, 1340, 1130 cm-1; H NMR (CDCl3) δ
7.42 (15H, m), 7.12 (1H, s), 6.98 (1H, s), 5.53 (1H, s), 4.95 (1H,
d, A of AB q, J ) 13 Hz), 4.65 (1H, d, B of AB q, J ) 13 Hz),
4.04 (1H, d, A of AB q, J ) 18 Hz), 3.77 (1H, d, B of AB q, J
) 18 Hz), 1.96 (3H, s); 13C NMR (CDCl3) δ 170.1 (s), 159.9 (s),
159.7 (s), 138.8 (s), 138.7 (s), 134.12 (s), 131.6 (d), 131.0, 129.8,
129.1, 128.4, 128.2, 128.1, 127.6, 127.0, 126.7, 126.2, 121.8 (d),
80.3 (d), 71.7 (d), 691.9 (t), 51.6 (t), 20.3 (q); high-resolution
mass spectrum for [C30H25NO7SNa]+, i.e. [M + Na]+, m/z calcd
566.1249, found 566.1262. Anal. (C30H25NO7S) C, H, N.
Ben zh yd r yl 7-[(E)-Ben zylid en e]cep h a losp or a n a te Su l-
fon e (12). This compound was prepared from the sulfide 11
(0.51 g, 1.0 mmol) as described for 5 to give a white solid (0.350
g, yield ) 65%): Rf ) 0.27 in CH2Cl2; mp 194-196 °C; IR
(CHCl3) 2975, 1775, 1730, 1340, 1125 cm-1; 1H NMR (CDCl3)
δ 8.00 (2H, m), 7.41 (13H, m), 7.03 (1H, s), 6.94 (1H, s), 5.24
(1H, s), 5.04 (1H, d, A of AB q, J ) 14 Hz), 4.70 (1H, d, B of
AB q, J ) 14 Hz), 4.05 (1H, d, A of AB q, J ) 18 Hz), 3.77 (1H,
d, B of AB q, J ) 18 Hz), 2.05 (3H, s); 13C NMR (CDCl3) δ
170.3 (s), 160.1(s), 157.7 (s), 138.9 (s), 138.8 (s), 138.5(d), 132.5,
131.5, 131.0, 128.9, 128.6, 128.3, 127.7, 127.1, 126.7, 122.8 (s),
80.4 (d), 69.5 (d), 62.1 (t), 51.2 (t), 20.5 (q); high-resolution mass
spectrum for [C30H25NO7SNa]+, i.e. [M + Na]+, m/ z calcd
566.1249, found 566.1248. Anal. (C30H25NO7S) C, H, N.
Ben zh yd r yl 7-(Dibr om om eth ylen e)cep h a losp or a n a te
(13). To the solution of Ph3P (12.0 g, 45.8 mmol) in anhydrous
CH2Cl2 (75 mL) was added CBr4 (7.6 g, 22.9 mmol) in one
portion at 0 °C. The mixture was stirred at room temperature
for 30 min. The reaction mixture was then cooled to -78 °C,
and a cold (-78 °C) solution of benzhydryl 7-oxocephalospo-
ranate 3 (5.00 g, 11.4 mmol) in anhydrous CH2Cl2 (40 mL) was
added. After 30 min of stirring at -78 °C, the reaction mixture
was concentrated in vacuo and purified by column chroma-
tography (CH2Cl2) to give a pale yellow solid (4.1 g, 61%
yield): Rf ) 0.55 in CH2Cl2; mp 58-60 °C; IR (CHCl3) 3030,
1780, 1745 cm-1; 1H NMR (CDCl3) δ 7.37 (10H, m), 6.96 (1H,
s), 5.19 (1H, s), 4.97 (1H, d, A of AB q, J ) 13 Hz), 4.72 (1H,
d, B of AB q, J ) 13 Hz), 3.52 (1H, d, A of AB q, J ) 18 Hz),
3.32 (1H, d, A of AB q, J ) 18 Hz), 2.00 (3H, s); 13C NMR
(CDCl3) δ 170.2 (s), 160.5 (s), 155.6 (s), 142.6 (s), 139.1 (s), 138.9
(s), 128.4, 128.0, 127.9, 127.0, 126.7, 125.2 (s), 92.6 (s), 79.9
(d), 63.0 (t), 60.1 (d), 27.0 (t), 20.5 (q). Anal. (C24H19Br2NO5S)
C, H, N.
Ben zh yd r yl 7-(Dibr om om eth ylen e)cep h a losp or a n a te
Su lfon e (14). This compound was prepared from the sulfide
15 as described above for 5 to yield a white solid (0.25 g,
79%): Rf ) 0.50 in 2% EtOAc in CH2Cl2; mp 62-64 °C; IR
(CHCl3) 3030, 1800, 1740, 1350, 1130 cm-1; 1H NMR (CDCl3)
δ 7.36 (10H, m), 6.95 (1H, s), 5.20 (1H, s), 5.03 (1H, d, A of AB
q, J ) 14 Hz), 4.68 (1H, d, B of AB q, J ) 14 Hz), 4.02 (1H, d,
A of AB q, J ) 18 Hz), 3.77 (1H, d, B of AB q, J ) 18 Hz), 2.02
(3H, s); 13C NMR (CDCl3) δ 170.1 (s), 159.6 (s), 154.8 (s), 138.8
(s), 138.7 (s), 135.2 (s), 128.6, 128.3, 127.5, 127.1, 126.4, 125.5
(s), 124.1 (s), 98.2 (s), 80.8 (d), 73.0 (d), 62.0 (t), 52.1 (t), 20.5
(q). Anal. (C24H19Br2NO7S) C, H, N.
Ben zh yd r yl 7-[(E)-Br om om eth ylen e]cep h a losp or a n -
a te (15). To a solution of 7-(dibromomethylene)cephalospo-
ranate 13 (1.19 g, 2 mmol) in methanol (20 mL) and THF (10
mL) was added NH4Cl (8.56 g, 16 mmol) in one portion at 0
°C. The mixture was stirred for 5 min. Zn/Cu (5.20 g, 8 mmol)
was added in one portion and further stirred at room temper-
ature for 30 min. The solvent was removed, and the residue
was extracted with ether (2 × 20 mL). The obtained ether
was washed with water (1 × 20 mL) and brine (1 × 10 mL),
mp 80-82 °C; IR (CHCl3) 3030, 1800, 1730, 1350, 1130 cm-1
;
1H NMR (CDCl3) δ 7.33 (10H, m), 6.94 (1H, s), 6.91 (1H, s),
5.10 (1H, s), 5.00 (1H, d, A of AB q, J ) 14 Hz), 4.67 (1H, d, B
of AB q, J ) 14 Hz), 3.97 (1H, A of AB q, J ) 18 Hz), 3.69 (1H,
d, B of AB q, J ) 18 Hz), 1.99 (1H, s); 13C NMR (CDCl3) δ
170.1 (s), 159.7 (s), 156.3 (s), 138.7 (s), 138.6 (s), 134.0 (s),
128.4, 128.1, 127.3, 126.9, 125.7, 124.9 (s), 112.5 (d), 80.57 (d),
70.9 (d), 61.8 (t), 51.2 (t), 20.4 (q). Anal. (C24H20BrNO7S) C,
H, N.
Ben zh yd r yl 7-[(Z)-(ter t-(Bu toxyca r bon yl)m eth ylen e]-
cep h a losp or a n a te (17). To a solution of benzhydryl 7-oxo-
cephalosporanate 2 (4.0 g, 9.2 mmol) in anhydrous CH2Cl2 (40
mL) at -78 °C was added a solution of [(tert-butoxycarbonyl)-
methylene]triphenylposphorane (3.45 g, 9.15 mmol in 40 mL
CH2Cl2). The mixture was then stirred at -78 °C for 30 min.
Acetic acid (1 mL) was added to quench the reaction, and the
reaction mixture was concentrated and purified by column
chromatography to give title compound as a pale yellow solid.
(yield ) 55%): Rf ) 0.52 in 2% EtOAc in CH2Cl2; mp 48-50
°C; IR (CHCl3) 3050, 1780, 1730 cm-1; 1H NMR (CDCl3) δ 7.36
(10H, m), 7.00 (1H, s), 6.39 (1H, s), 5.47 (1H, s), 5.00 (1H, d,
A of AB q, J ) 13.48 Hz), 4.77 (1H, d, B of AB q, J ) 13.48
Hz), 3.62 (1H, d, A of AB q, J ) 18 Hz), 3.38 (1H, d, B of AB
q, J ) 18 Hz), 2.02 (3H, s), 1.54 (9H, s); 13C NMR (CDCl3) δ
170.2 (s), 162.4 (s), 160.5 (s), 157.8 (s), 150.1, (s), 139.0 (s),
138.8 (s), 128.3, 128.0, 127.9, 127.5, 126.9, 125.0 (s), 119.9 (d),
82.9 (s), 79.7 (d), 62.8 (t), 57.5 (d), 28.0 (q), 27.9 (t), 20.4 (q).
Anal. (C29H29NO7S) H, N; C: calcd, 65.05; found, 64.50.
Ben zh yd r yl 7-[(Z)-(ter t-Bu toxyca r bon yl)m eth ylen e]-
cep h losp or a n a te Su lfon e (18). This compound was pre-
pared from the corresponding sulfide 17 as described above
for 5 to give a white solid (yield ) 73%): Rf ) 0.68 in 5% EtOAc
in CH2Cl2; mp 58-60 °C; IR (CHCl3) 3025, 1800, 1730, 1350,
1160 cm-1; 1H NMR (CDCl3) δ 7.36 (10H, m), 6.98 (1H, s), 6.59
(1H, s), 5.58 (1H, s), 5.14 (1H, d, A of AB q, J ) 14 Hz), 4.80
(1H, d, B of AB q, J ) 14 Hz), 4.12 (1H, d, A of AB q, J ) 18
Hz), 3.77 (1H, d, B of AB q, J ) 18 Hz), 2.04 (3H, s), 1.52 (9H,
s); 13C NMR (CDCl3) δ 170.0 (s), 161.5 (s), 159.4 (s), 157.1 (s),
142.3 (s), 138.6 (s), 138.5 (s), 128.8, 128.4, 128.3, 127.2, 127.0,
125.9 (s), 123.5 (d), 83.8 (s), 80.2 (d), 71.6 (d), 61.3 (t), 52.8 (t),
27.6 (q), 20.2 (q); high-resolution mass spectrum for [C29H29
-
NO9SNa]+, i.e. [M + Na]+, m/ z calcd 590.1461, found 590.1447.
Anal. (C29H29NO9S) C, H, N.
Ben zh yd r yl 7-[(Z)-F or m ylm eth ylen e]cep h a losp or a n -
a te (19). This compound was prepared from 2 and (triphen-
ylphosphoranylidene)acetaldehyde using the procedure de-
scribed for the preparation of compound 17 (yield ) 46%): Rf
) 0.37 in 2% EtOAc in CH2Cl2; mp 113-115 °C; IR (CHCl3)
1
3050, 1780, 1730, 1700 cm-1; H NMR (CDCl3) δ 9.80 (1H, d,
J ) 6.1 Hz), 7.34 (10H, m), 6.99 (1H, s), 6.60 (1H, d, J ) 6.1
Hz), 5.45 (1H, s), 5.00 (1H, d, A of AB q, J ) 13.51 Hz), 4.75
(1H, d, B of AB q, J ) 13.55 Hz), 3.64 (1H, d, A of AB q, J )
18.59 Hz), 3.41 (1H, d, B of AB q, J ) 18.61 Hz), 2.00 (3H, s);
13C NMR (CDCl3) δ 188.2 (d), 170.1 (s), 160.3 (s), 157.0 (s),
154.7 (s), 138.9 (s), 138.8 (s), 128.4, 128.1, 128.0, 127.6, 126.9,
126.7, 125.0 (s), 123.5 (d), 79.9 (d), 62.4 (t), 56.4 (d), 28.1 (t),
20.4 (q); high-resolution mass spectrum for [C25H21NO6SNa]+,
i.e. [M + Na]+, m/ z calcd 486.0987, found 468.0981. Minor
product E-isomer; 1H NMR (CDCl3) d 10.28 (1H, d, J ) 7.6
Hz), 7.34 (10H, m), 6.99 (1H, s), 6.26 (1H, d, J ) 7.6 Hz), 5.28
(1H, s), 5.00 (1H, d, A of AB q, J ) 13.5 Hz), 4.75 (1H, d, B of
AB q, 13.5 Hz), J ) 3.60 (1H, d, A of AB q, J ) 18.6 Hz), 3.40