6846
J. Am. Chem. Soc. 1998, 120, 6846-6847
Scheme 1
Synthesis of the First 2′,6 Bridged Penams
John D. Buynak,* A. Srinivasa Rao, Greg Adam,
Sirishkumar D. Nidamarthy, and Hongming Zhang
Department of Chemistry
Southern Methodist UniVersity
Dallas, Texas 75275-0314
ReceiVed January 20, 1998
The reactivity of â-lactams toward nucleophiles in non-
enzymological systems can be determined by a number of factors,
including both the electronic and steric nature of substituents on
the ring1 as well as the pyrimidality of the â-lactam nitrogen.
Particularly in the penam, penem, and carbapenem systems (1),
the fusion of the â-lactam to a five-membered ring enhances the
susceptibility of the â-lactam carbonyl toward nucleophiles by a
factor of approximately 100.1 A simultaneous increase in the
stretching frequency of the carbonyl group suggests that the added
reactivity is caused by a partial pyrimidalization of the normally
planar amide nitrogen. A more dramatic example of such
pyrimidalization occurs in bridgehead lactams of type 2, which
have been referred to as “anti-Bredt”, by analogy with the
corresponding alkenes.2 Williams and Lee have synthesized and
examined the stability of 1,3-bridged-2-azetidinones (3).3
tion and evaluation of a number of new penam- and cephem-
derived inhibitors of â-lactamase6 and elastase,7 and we were
interested in investigating the inhibitory potential of structures
such as 5. General structure 5 also provides a unique opportunity
to explore the limits of strain in the penicillin series. We now
report the synthesis of the first 2′,6 bridged penams.
As shown in Scheme 1, benzhydryl and benzyl esters of
6-aminopenicillanic acid were protected by reaction with allyl
chloroformate (R ) Bhl or Bn, yields are shown for the
benzhydryl series). The resultant urethanes were then oxidized
to afford (>90%) the (S)-sulfoxide isomer (and a small amount
of the opposite diastereomer). The directing effect of the 6-amido
group in this oxidation has been noted previously.8 Treatment
of this sulfoxide with 2-mercaptobenzothiazole produced a
quantitative yield of disulfide 10.9 Cyclization of 10 by treatment
with silver acetate in the presence of excess chloroacetic acid10
produced a 3:1 mixture of the 2′â-substituted penam (11) and
3â-substituted cephalosporin (12) as shown. Even when stored
Recently 2′â-substituted penams, such as tazobactam (4),4 have
attracted attention as efficient inhibitors of class A â-lactamases,
hydrolytic enzymes which are responsible for bacterial resistance
to the â-lactam antibiotics. In our survey of the literature, we
were surprised by the absence of any penam-type structures
incorporating an additional bridge between the 2′â and the 6
positions, which are normally situated in close proximity on the
concave face of this system (general structure 5). Recent
theoretical calculations on related hypothetical bridged tricyclic
compounds such as 6, suggested that the highly pyrimidal nitrogen
might allow such compounds to serve as transition-state analogues
for proteolytic processes.5 We had recently reported the prepara-
(1) (a) Rao, S. N.; O’Ferrall, R. A. M. J. Am. Chem. Soc. 1990, 112, 2729-
2735. (b) Procter, P.; Gesmantel, N. P.; Page, M. I. J. Chem. Soc., Perkin
Trans. 2 1982, 1185-1192.
(2) (a) Lukes, R. Collect. Czech. Chem. Commun. 1939, 10, 148. (b) Hall,
H. K.; El-Shekeil, A. Chem. ReV. 1983, 83, 549-555. (c) Pracejus, H.; Kehlen,
M.; Kehlen, H.; Matschiner, H. Tetrahedron 1965, 21, 2257. (d) Greenberg,
A.; Venanzi, C. A. J. Am. Chem. Soc. 1993, 115, 6951-6957. (e) Greenberg,
A. In Structure and ReactiVity: Liebman, J. F., Greenberg, A., Eds.; VCH:
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Bachmann, B.; Khasnis, D.; Hua, L.; Nguyen, H. K.; Carver, C. L. J. Med.
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Winkler, F. K. J. Med. Chem. 1996, 39, 3712-3722.
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S0002-7863(98)00195-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/26/1998