Synthesis of the first 2',6 bridged penams

Full text of DOI:10.1021/ja980195z

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:
New York, 1988; Vol. 7, Chapter 4.
(6) (a) Buynak, J. D.; Khasnis, D.; Bachmann, B.; Wu, K.; Lamb, G. J.
Am. Chem. Soc. 1994, 116, 10955-10965. (b) Buynak, J. D.; Wu, K.;
Bachmann, B.; Khasnis, D.; Hua, L.; Nguyen, H. K.; Carver, C. L. J. Med.
Chem. 1995, 38, 1022-1034. (c) Buynak, J. D.; Geng, B.; Bachmann, B.;
Hua, L. Bioorg. Med. Chem. Lett. 1995, 5, 1513-1518.
(7) Buynak, J. D.; Rao, A. S.; Ford, G. P.; Carver, C.; Adam, G.; Geng,
B.; Bachmann, B.; Shobassy, S.; Lackey, S. J. Med. Chem. 1997, 40, 3423-
3433.
(3) (a) Williams, R. M.; Lee, B. H. J. Am. Chem. Soc. 1986, 108, 6431-
6433. (b) Williams, R. M.; Lee, B. H.; Miller, S.; Anderson, O. P. Spec. Publ.,
R. Soc. Chem. 1989, 70, 106-118.
(4) (a) Bush, K.; Macalintal, C.; Rasmussen, B. A.; Lee, V. J.; Yang, Y.
Antimicrob. Agents Chemother. 1993, 37, 851-858. (b) Richter, H. G. F.;
Angehrn, P.; Hubschwerlen, C.; Kania, M.; Page, M. G. P.; Specklin, J. L.;
Winkler, F. K. J. Med. Chem. 1996, 39, 3712-3722.
(8) (a) Morin, R. B.; Jackson, b. G.; Mueller, R. A.; Lavagnino, E. R.;
Scanlon, W. B.; Andrews, S. L. J. Am. Chem. Soc. 1963, 85, 1869. (b) Cooper,
R. D. G.; Hatfield, L. D.; Spry, D. O. Acc. Chem. Res. 1973, 6, 32. (c) Adam,
S.; Arnold, W.; Schonholzer, P. Tetrahedron 1983, 39, 2485-2491.
(9) Kamiya, T.; Teraji, T.; Saito, Y.; Hashimoto, M.; Nakaguchi, O.; Oku,
T. Tetrahedron Lett. 1973, 14, 3001-3004.
(5) (a) Bruton, G. Bioorg. Med. Chem. Lett. 1993, 3, 2329-2332. (b) Reddy,
N. A. V.; Setti, E.; Phillips, O. A.; Czajkowski, D. P.; Atwal, H.; Atchison,
K.; Micetich, R. G.; Maiti, S. N.; Kunugita, C.; Hyodo, A. J. Antibiot. 1997,
50, 276-278.
(10) Baldwin, J. E.; Dobb, J. E.; Sheppard, L. N. Tetrahedron 1987, 43,
1003-1012.
S0002-7863(98)00195-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/26/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 27, 1998 6847
Scheme 2
Figure 1. Perspective view of 16 showing the atom-numbering scheme
with thermal ellipsoids drawn at the 40% probability level. For clarity,
all H atoms, as well as the carbons of the aromatic residues, are drawn
with circles of arbitrary radii.
These compounds are 1,3-bridged-2-azetidinones similar to 3,
with an extra link between the bridge and the 4-position of the
azetidinone (this link being represented by the 1-position sulfur
of the penam). Relative to other 1,3-bridged-2-azetidinones, this
additional linkage may actually stabilize the â-lactam carbonyl
toward reaction with nucleophiles by increasing the planarity of
the azetidinone nitrogen. In support of this, it should be noted
that an attempt to remove the sulfur by heating 15 (R ) Bn)
with tributyltin hydride in the presence of AIBN was unsuccessful,
resulting in only decomposition of the starting material.
Unfortunately, these compounds did not display appreciable
activity as inhibitors of representative class A (TEM-1) or class
C (P99) serine-based â-lactamases.13 Biological screening as
inhibitors of other proteases is in progress. A wide variety of
substituted bridged penams should be available using this synthetic
methodology.
at -20 °C, this mixture gradually equilibrated to the cepha-
losporin. This transformation is believed to involve the episul-
fonium ion shown.11
The mixture was thus immediately deprotected by treatment
with Pd° in the presence of tributyltin hydride, and the mixture
of resultant amines was heated in DMSO to produce the desired
cyclized compound 15 in 29% yield. Attempts to perform a
similar cyclization on the corresponding sulfoxide failed. To
further demonstrate the thermal stability of this unusual tricyclic
system, 15 (R ) Bhl) was heated to 100 °C in DMSO-d6 for 12
Acknowledgment. This research was supported by grants from the
Robert A. Welch Foundation and from the Petroleum Research Fund
administered by the American Chemical Society.
Supporting Information Available: Tables of positional and thermal
parameters, selected bond distances and angles, anisotropic displacement
factors, and H atom coordinates and isotropic displacement parameters
for 16 and experimental procedures for the transformations of 10 to 15
(7 pages, print/PDF). See any current masthead page for ordering
information and Web access instructions.
1
h with no detectable change in the H NMR spectrum.
This secondary amine could be functionalized in a number of
ways (Scheme 2). In particular, it was treated with phenylacetyl
chloride to produce the corresponding tertiary amide (16) and
deprotected or, alternatively, oxidized to the corresponding sulfone
and deprotected. Similarly, reactions with phenyl isocyanate
produced the urea which could also be deprotected as either the
sulfide or sulfone. Although these carboxylate salts were stable
in aqueous solution, when the benzhydryl ester 16 was stirred in
methanol at room temperature for 14 h, cleavage of the â-lactam
occurred to produce 24.
JA980195Z
(12) [C31H28N2O6S]‚[C6H6], formula weight 634.7, crystallized in an
orthorhombic system, P212121, a ) 6.215(3), b ) 17.174(5), and c ) 31.074-
(10) Å, V ) 3317(2) Å3, Z ) 4, d ) 1.271 Mg/m3, µ ) 0.146 mm-1. Data
were collected on a Siemens P4 diffractometer at -45°, Mo KR, 2θ 3.0-
42.0°; 2058 reflections were collected. Data were corrected for Lorentz and
polarization effects, but not for absorption. The structure was solved with
direct methods and refined on F2 (G. M. Sheldrick, SHELX93, University of
Go¨ttengen, Germany, 1993). All non H atoms were anisotropically refined,
while H atoms were located on a “riding model”. The final refinement
converged at R ) 0.068, wR2 ) 0.135, GOF ) 1.02 for 1742 observed
reflections (I > 2.0σ(I)].
An X-ray crystal structure of compound 16 was obtained,12
verifying the tricyclic nature of these compounds (Figure 1).
(13) In each case, the IC50 values of these bridged analogues were evaluated
as greater than 1 mM, relative to a measured value for tazobactam of 0.3 µM
for TEM-1 and 50 µM for P99.
(11) For a leading reference, see: Balsamo, A.; Benedini, P. M.; Macchia,
B.; Macchia, F.; Rossello, A. J. Chem. Soc., Perkin Trans. 1 1984, 413-417.