320
LETTERS
SYNLETT
acylation with remarkable regio- and stereoselectivity. On mechanistic
grounds we inferred that benzoylation took place from the cephem β-
face; but NOE experiments, being inconclusive, failed to corroborate
Acknowledgements: We wish to thank the Analytical Department (Dr.
Daniela Borghi and Dr. Emanuele Arlandini) for their support in
providing spectroscopic data. Finally, we would like to thank Mr.
Edgardo Poma and Mr. Antonio Fiumanò for technical assistance.
13
our hypothesis.
Two ways were considered for transforming 7 into 1: i) removal of the
carboxy protecting group, decarboxylation and sulfur oxidation or ii)
References and Notes
oxidation first, followed by deprotection and CO extrusion. Both
2
1)
2)
3)
4)
Morin, R.B.; Gorman, N. Chemistry and Biology of β-Lactam
Antibiotics, Academic Press: New York, 1982, Vol. 1, 2 and 3.
pathways were found viable, but ii) was preferred for requiring less
stringent conditions in the decarboxylative step. In fact, we succeeded in
performing a satisfactory conversion of 7 into 5 only by employing
Mascaretti, O.A.; Boschetti, C.E.; Danelon, G.O.; Mata, E.G.;
Roveri, O.A. Current Medicinal Chemistry 1995, 1, 441.
aluminum trichloride at low temperature (AlCl 1.5 mol equiv; anisole-
3
Alpegiani, M.; Bissolino, P.; Perrone, E. Trends in Organic
Chemistry 1995, 3, 203.
dichloromethane, -45°C, 64% yield); while a similar transformation of
cephem sulfone 8 into target 1, in addition to taking place excellently
Alpegiani, M.; Bissolino, P.; Corigli, R.; Del Nero, S.; Perrone,
E.; Rizzo, V.; Sacchi, N.; Cassinelli, G.; Franceschi, G.; Baici, A.
J. Med. Chem. 1994, 37, 4003.
using the AlCl protocol (>85% yield), could also be realised under
3
more practical conditions (CF COOH/CH Cl 1:4; 1 h, 60-65% yield).
3
2
2
Smooth sulfide to sulfone oxidation with m-chloroperbenzoic acid
(MCPBA 2.5 mol equiv; EtOAc) occurred both on 5 and on 7, providing
5)
6)
7)
Alpegiani, M.; Bissolino, P.; Corigli, R.; Rizzo, V.; Perrone, E.
BioMed. Chem. Lett. 1995, 5, 687; ibidem 1995, 5, 691.
16
1 and 8 respectively in high yields (85-90%).
The above described procedure, encompassing acylation of 6 with the
proper acyl chloride, sulfur oxidation, removal of the protecting group
and simultaneous loss of carbon dioxide, was successfully extended to
the preparation of a series of cephem-4-yl aryl ketones. Representative
examples, including α-naphthyl and β-naphthyl ketones 9 and 10,
biphenylyl derivative 11 and 4-(4-benzoylbenzoyl)cephem 12 are
shown in Scheme 3.
Alpegiani, M.; Bissolino, P.; D’Anello, M.; Palladino, M.;
Perrone, E.: Synlett 1998, 322.
Alpegiani, M.; Bissolino, P.; D’Anello, M.; Rivola, G.; Borghi,
D.; Perrone, E. Tetrahedron Lett. 1991, 32, 3883.
8)
9)
Kuhlein, K.; Jensen, H. Liebigs Ann. Chem. 1974, 369.
Alpegiani, M.; Bissolino, P.; Borghi, D.; Sbraletta, P.; Tonani, R.;
Perrone, E. Heterocycles 1993, 36, 1747.
10) Alternative efficient protections of acid 3 were effected with p-
nitrobenzyl bromide (NEt , DMF) and methyl iodide (NaHCO ,
3
3
DMF), but the corresponding esters gave unsatisfactory results
during acylation (with PNB ester) or removal of the protecting
group (Me ester).
11) Discussion of the spectroscopic features which allowed structural
3
2
assignments of the prepared ∆ - and ∆ - cephems have been
detailed in our previous work (see in particular Ref. 9 and 12).
12) Alpegiani, M.; Bissolino, P.; Borghi, D.; Perrone, E. Synlett 1994,
4, 233.
Scheme 3
13) By analogy with the alkylation of cephem esters, the electrophilic
species (benzoyl chloride in this case) should attack from the more
hindered cephem β−face on the basis of electronic grounds
(repulsion between the α-oriented lone pair of N and that of C-4 in
In most instances, following acylation of cephem 6, only minor
contaminants accompanied the formation of diacyl cephems 13. Small
amounts (<5%) of ∆ -cephems acylated at C-7 were often detected
and isolated after MCPBA oxidation (14, R=biphenylyl, α- and β-
naphthyl); in one instance a minimal quantity of a product (15) arising
from double acylation (both at C-7 and C-4) was observed.
3
17
9,14,15.
the carbanion intermediate).
14) Bremner, D.H.; Campbell, M.C. J. Chem. Soc., Perkin Trans. I
1977, 2298.
15) Yoshida, A.; Oida, S.; Ohki E. Chem. Pharm. Bull. 1975, 23,
2507.
16) All compounds were fully characterised by spectroscopic means.
Selected experimental and spectral data are given below:
3
p-Methoxybenzyl
late (6). To
7α-methoxy-3-methyl-∆ -cephem-4-carboxy-
a
suspension
of
7β-amino-3-
deacetoxycephalosporanic acid (20 g, 93.4 mmol) in CH OH
3
(1200 ml), cooled to -5°C, methanesulfonic acid (38.8 ml, 0.6
mol) was added dropwise in 10 min. Sodium nitrite (38.6 g, 0.56
mol) was then added and the resulting mixture was stirred at r.t.
for 21 h. After addition of sodium bicarbonate (3.14 g, 37.4
mmol) and stirring for 15 min, the mixture was filtered over celite.
The filtrate was concentrated under vacuum to one fourth of its
Finally, we tried to make use of the aforementioned methodology for
preparing t-butyl ketone 2, but only unreacted starting material could be
recovered when 6 was exposed to the action of LDA and then pivaloyl
chloride. While in this case the steric hindrance of the electrophilic
agent might prevent the acylation from occurring, yet the reaction with
less encumbered aliphatic acyl halides deserves investigation.
initial volume, diluted with CH Cl (300 ml), and washed with an
2
2
acidic (pH 2, 1000 ml) aqueous solution saturated with NaCl. The
aqueous layer was re-extracted with CH Cl (2x300 ml). The
2
2
organic phase was dried (Na SO ) and concentrated under
2
4
3
reduced pressure to give crude 7α-methoxy-3-methyl-∆ -cephem-
Alpegiani, Marco
