Cephalosporin G Amide (6). A solution of 1 (3.4 g, 10.2 mmol) in THF (80 mL) was cooled to -35°C and treated
with Et N (1.42 mL, 10.4 mmol) and isobutylchloroformate (1.42mL, 10.4mmol). Aprecipitateoftriethylamine hydrochloride
3
started to form after 1-2 min. The mixture was stirred at this temperature for 25 min and treated with a solution of saturated
aqueous ammonia (2 mL) in water (8 mL). Triethylamine hydrochloride dissolved. A white crystalline precipitate began to
form after 1 min. The mixture was stirred for 25 min at -15°C. The precipitate was filtered off and washed with methanol,
+
acetone, and ether to afford 6 (2.82 g, 83%), white crystalline powder, mp 258-261°C. Mass spectrum (CCA, m/z): 331 [M] .
1
2
PMR spectrum (DMSO-d , δ, ppm, J/Hz): 1.98 (3H, s, CH ), 3.295 (1H, d, J = 18, H -2), 3.46 (1H, d, J = 18, H -2), 3.52 (1H,
6
3
1
2
d, J = 13.5, PhCH ), 3.61 (1H, d, J = 13.5, PhCH ), 4.926 (1H, d, J = 5, H-6), 5.49 (1H, dd, J = 5, J
= 8.5, H-7), 7.28 (5H,
(NH)H
m, Ph), 7.47 (2H, d, J = 96.5, NH ), 9.05 (1H, d, J
= 8.5, NH).
2
(NH)H
Cephalosporin G L-Glutamic Acid Amide Dipotassium Salt (7). A solution of 1 (5.1 g, 15.3 mmol) in THF
(120 mL) was cooled to -35°C and treated successively with Et N (2.2 mL, 16.1 mmol) and isobutylchloroformate (2.2 mL,
3
16.8 mmol). A precipitate of triethylamine hydrochloride began to form after 1.5-2 min. The mixture was stirred for 40 min,
allowing the temperature to rise to 15°C, then diluted with cold water (50 mL) and extracted with ethylacetate (400 mL). The
organic layer was separated; washed with saturated NaHCO solution, water, and brine; and dried over Na SO . The desiccant
3
2
4
was filtered off. The filtrate was evaporated to afford the solid mixed anhydride of 1 and isobutylformate (5.9 g). The resulting
anhydride was dissolved in methanol (270 mL), stirred, and treated in one portion with a mixture of L-Glu (1.68 g, 11.3 mmol)
and K CO (1.656 g) in water (12 mL). The resulting transparent solution developed a white precicpitate after several minutes
2
3
and was stirred at room temperature for 50 min. The precipitate was filtered off, washed with methanol and ether, and dried
in vacuo to afford 7 (5.92 g, 74%), white crystals, mp 245-246°C (dec.). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 1.668 (1H,
6
1
m, H-2′), 1.899 (1H, m, H-2′), 1.917 (3H, s, CH ), 2.166 (1H, ddd, H-3′), 2.337 (1H, ddd, H-3′), 3.267 (1H, d, J = 18, H -2),
3
2
1
2
3.49 (1H, d, J = 18, H -2), 3.50 (1H, d, J = 13, PhCH ), 3.57 (1H, d, J = 13, PhCH ), 4.152 (1H, ddd, H-1′), 4.99 (1H, d,
J = 5, H-6), 5.55 (1H, dd, J = 5, J = 8.5, H-7), 7.281 (5H, m, Ph), 7.61 (1H, d, J = 7, CONH), 9.04 (1H, d,
(NH)H
(NH)H
J
= 8.5, BnCONH).
(NH)H
Cephalosporin G L-Arginine Amide (8). A solution of 1 (3.4 g, 10.2 mmol) in THF (80 mL) was cooled to -35°C
and treated successively with Et N (1.42 mL, 10.4 mmol) and isobutylchloroformate (1.42 mL, 10.4 mmol). A precipitate of
3
triethylamine hydrochloride began to form after 1.5-2 min. The mixture was stirred for 25 min and treated with a solution of
L-arginine (1.83 g, 10.5 mmol) in water (11 mL). Triethylamine hydrochloride dissolved. A white crystalline precipitate began
to form after 1 min. the mixture was stirred for 25 min at -15°C. The resulting precipitate was filtered off and washed with
methanol, acetone, and ether to afford 8 (3.59 g, 72%), white crystalline powder, mp 242-245°C. PMR spectrum (DMSO-d ,
6
δ, ppm, J/Hz): 1.53 (2H, m, H -3 ), 1.68 (1H, m, H-2′), 1.75 (1H, m, H-2′), 1.968 (3H, s, CH ), 3.03 (2H, m, H -4′), 3.28 (1H,
2
3
2
1
2
1
2
d, J = 17.5, H -2), 3.39 (1H, d, J = 17.5, H -2), 3.50 (1H, d, J = 14, PhCH ), 3.57 (1H, d, J = 14, PhCH ), 4.01 (1H, ddd, H-1′),
4.93 (1H, d, J = 4.5, H-6), 5.5 (1H, dd, J = 4.5, J = 8.5, H-7), 7.29 (5H, m, Ph), 7.74 (1H, d, J = 7.5, CONH), 9.0
(NH)H
(NH)H
(1H, d, J
= 8.5, BnCONH), 9.1 (1H, m, NH-1′).
(NH)H
Cephalosporin G Acid Fluoride (9). Asuspension oftris-morpholinotrimethyldifluorosilicate(1.5g)in THF (60 mL)
at -50°C was stirred, treated with morpholinotrifluorosulfurane (6 mL) and dropwise with 1 (6 g, 18 mmol) in THF (60 mL),
stirred for 30 min at -50°C, poured into water (200 mL), and extracted with ethylacetate (500 mL). The organic layer was
separated, washed with water and brine, and dried over anhydrous Na SO . The desiccant was filtered off. The filtrate was
2
4
evaporated. The solid was dissolved in CHCl and purified by column chromatography over silica gel with elution by CHCl
3
3
and CHCl :CH COCH (10:1). Fractions containing the acid fluoride were combined and evaporated. The solid was dissolved
3
3
3
in acetone and diluted with three volumes of ether and two volumes of hexane. The resulting white powder was filtered off,
19
washed with ether, and dried to afford 9 (4.5 g, 75%). F NMR (CDCl ): -110.9. PMR spectrum (CDCl , δ, ppm): 2.04 (3H,
3
3
s, CH ), 3.45 (4H, m, PhCH , H -2), 5.05 (1H, d, H-6), 5.62 (1H, m, H-7), 7.26 (5H, m, Ph), 9.14 (1H, d, NH).
3
2
2
REFERENCES
1.
2.
3.
4.
5.
6.
Yu. A. Ovchinnikov, Bioorganic Chemistry [in Russian], Prosveshchenie, Moscow (1987).
R. D. Beger, Drug Discovery Today, 11, 429 (2006).
J.-L. Pan and M.-J. Syu, Biochem. Eng. J., 23, 203 (2005).
J. W. Grant and T. P. Smyth, J. Org. Chem., 69, 7965 (2004).
X. Tang, T. Cai, and P. G. Wang, Bioorg. Med. Chem. Lett., 13, 1687 (2003).
L. N. Markovskij, V. E .Pashinnik, and A. V. Kirsanov, Synthesis, 6, 787 (1973).
106