Bioorganic & Medicinal Chemistry Letters 10 (2000) 1389±1391
Synthesis and Biological Activities of an ꢀ-Methyl and a ꢁ-Methyl
Carbapenem and the Corresponding Unsubstituted Compoundy
Hans Rudolf Pfaendler,* Ralf Weishaupt and Helmut Meert
Department of Chemistry, University of Munich, Butenandtstr. 5 13, 81377 Munich, Germany
Received 11 February 2000; accepted 26 April 2000
AbstractÐThe carbapenem potassium salts 4, 7 and 8 were prepared. Their rates of b-lactam hydrolysis and their biological activ-
ities, particularly their b-lactamase inhibiting properties, were examined and explained on the basis of their dierent substitution
and pyramidality. # 2000 Elsevier Science Ltd. All rights reserved.
Carbapenems are broad spectrum antibiotics with high
activity against Gram-positive and Gram-negative bac-
teria.1 Because of their strained bicyclic ring system they
are very reactive. Investigations have shown that a b-
methyl group in position 1 of the bicyclic molecule has a
stabilizing in¯uence without signi®cantly decreasing the
biological activity.2 In contrast, an a-methyl group in
position 1 decreases the antibiotic potential.3 Conse-
quently, to achieve higher antibiotic activity, most endea-
vours were focused on the b-methyl series. Concerning the
activity as b-lactamase inhibitors, investigations have also
been limited to the b-methyl and 1-unsubstituted deri-
vatives.4 Surprisingly, as far as we know, an a-methyl
carbapenem has never been examined in this context.
Then they were both hydrogenolyzed in EtOAc with 10%
Pd on C as catalyst to remove the p-nitrobenzyl protective
group. This reaction has to be carried out with care in order
to avoid hydrogenation of the CC double bond. There-
fore, the hydrogen absorption was observed permanently.
The reaction was stopped slightly before consumption of
the expected amount of hydrogen (4 equiv). The reaction
mixture was then ®ltered at 0 ꢀC and the ®ltrate extracted
with 1 equiv of KHCO3 in water. Compounds 4 and 7
were obtained in aqueous solutions in 100% and 58%
yields, respectively, as determined by UV-spectroscopy.7
According to HPLC,8 the purity of 4 and 7 was higher
than 97%. The carbapenem 8, which is unsubstituted in
position 1, was prepared in an analogous way (Scheme 1).
1-b-Methyl carbapenam 2 is an intermediate of many car-
bapenem syntheses. It is known that 2 can undergo a par-
tial epimerisation to the corresponding a-methyl isomer
during a silica gel column chromatography.5 This proce-
dure was used to prepare the 1-a-methyl carbapenam 5.
Table 1 shows the half-lives of hydrolysis of the carba-
penem potassium salts 4, 7 and 8 under physiological
conditions (pH=7.4, 37 ꢀC), as determined by UV-
spectroscopy.
The pyramidality at the b-lactam nitrogen atom has
often been used to explain the reactivity of bicyclic b-
lactams.9 11 When compared to the 1-unsubstituted
carbapenem 8, the pyramidality at the b-lactam nitro-
gen decreases with a b-methyl substitution. In other
words, the b-methyl group ¯attens the bicyclic structure,
whereas the a-methyl substitution does not aect the
folding noticeably. Therefore the half-lives of hydrolysis
of 7 and 8, being in the same order of magnitude, as well
as that of 4, being signi®cantly higher, can be explained
on this basis (Table 1; see also Scheme 2).
Starting with 1, the carbapenam 2 was prepared by the
known cyclisation reaction with Rh2(OAc)4 as cata-
lyst.2,3,6 Subsequently, 2 was chromatographed several
times to give pure a-methyl compound 5. The prepara-
tion of 5 is even easier by stirring 2 in EtOAc with SiO2
at rt for about 2 h, aording better yields. Likewise, the
pure isomeric 5 could be obtained after ®ltration and
evaporation under reduced pressure.
The b- as well as the a-methyl compounds could be
methylated to the carbapenems 3 and 6 with diazomethane.
Another important in¯uence is exercised by steric hin-
drance. It is known, that a serine residue of penicillin
binding proteins (PBPs) and b-lactamases open the b-lac-
tam ring of bicyclic b-lactam antibiotics from the a-side.
*Corresponding author. Fax: +89-5902-483;
e-mail: hrp@orf.chemie.uni-muenchen.de
yDedicated to Professor Rolf Huisgen on the occasion of his 80th
birthday.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00248-1