Studies on nonconventionally fused bicyclic β-lactams

Article abstract of DOI:10.1021/jo9811219

Described in this article are studies of structurally novel [3.2.0]bicyclic β-lactam ring systems that are isomeric to those of the penicillin, penem, and clavulanic acid families of antibiotics, but which have the lactam functionality arranged in alterna

Full text of DOI:10.1021/jo9811219

8898
J . Org. Chem. 1998, 63, 8898-8917
Stu d ies on Non con ven tion a lly F u sed Bicyclic â-La cta m s
Xiao-Feng Ren,1 Monika I. Konaklieva,1 Hongchang Shi,2 Sonja Dickey,3 Daniel V. Lim,3
J avier Gonzalez,4 and Edward Turos*,5
Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260,
Department of Biology, University of South Florida, Tampa, Florida 33620,
Departamento de Quimica Organica e Inorganica, Universidad de Oviedo, 33071-Oviedo, Spain, and
Department of Chemistry, University of South Florida, Tampa, Florida 33620
Received J une 11, 1998
Described in this article are studies of structurally novel [3.2.0]bicyclic â-lactam ring systems that
are isomeric to those of the penicillin, penem, and clavulanic acid families of antibiotics, but which
have the lactam functionality arranged in alternative orientations within the four-membered ring.
Semiempirical calculations indicate that the thermodynamic stabilities of the three alternative
isomeric ring systems are similar to that of the classical penam or penem structure, and ab initio
methods reveal that the LUMO energies of the two C-fused ring structures 11 and 12 are more
than 1 eV lower than that of 2-azetidinone, but 0.22 to 0.73 eV higher than that of the penem ring
13. The LUMO energy of the N-S fused penem structure 14 is about 0.2 eV lower than that of 13.
These studies also suggest that the N-fused bicyclic â-lactams are considerably more electrophilic
than the corresponding C-fused compounds. Several of the new heterocyclic rings were synthesized
using a two-step cyclization strategy to assemble the bicyclic core. First, the â-lactam ring was
created by a Staudinger reaction of an acid chloride and R,â-unsaturated imine, and the sulfur
heterocycle was closed through a halogen-promoted cyclization reaction of a sulfur substituent onto
a neighboring alkenyl or alkynyl side chain. Using palladium catalysis, iodopenem adducts 18,
31a , and 56a were converted to vinyl- and heteroaryl-substituted derivatives, carboxylic esters,
and carboxylic acids. Four of the bicyclic â-lactams prepared in this study (58b, 80, 87, and 89)
showed weak levels of activity against Staphylococcus aureus or Vibrio cholerae.
In tr od u ction
structural relatives possess the unusual ability to inter-
rupt this crucial cross-linking event by acylating the
catalytic serine unit within the enzyme active site,
resulting in bacteria having weakened or poorly formed
cell walls. Over the years, numerous penicillin deriva-
tives9 have been prepared and examined for antibacterial
activity. Additionally, a variety of new â-lactam-contain-
ing ring systems isolated from natural sources or from
synthetic laboratories have been reported, including the
penems,10 carbapenems,11 cephalosporins,12 clavulanic
Since the advent of penicillin, the â-lactam antibiotics
have been the subject of much discussion and investiga-
tion, within both the scientific and public sectors.6 More
recently, â-lactam compounds have become attractive
starting materials and intermediates in a wide range of
synthetic7 settings and have demonstrated potential as
inhibitors of various proteolytic enzyme systems.8 The
primary biological targets of the â-lactam drugs are the
penicillin binding proteins, a group of transpeptidases
anchored within the bacterial cellular membrane which
mediate the final step of cell wall biosynthesis. In a key
biochemical step, the D-alanine-D-alanine terminus of a
peptidoglycan strand is enzymatically cleaved by a
transpeptidase, and joined to another peptidoglycan
residue within the bacterial cell wall. Penicillin and its
(9) (a) M. L. Sassiver; Lewis, A. In Structure-Activity Relationships
Among the Semisynthetic Antibiotics; Perlman, D., Ed.; Academic
Press: New York, 1977; pp 87-160. (b) Recent Advances in the
Chemistry of Anti-Infective Agents; Bentley, P. H., Ponsford, R., Eds.;
The Royal Society of Chemistry: Cambridge, 1993. (c) Guthikonda,
R. N.; Cama, L. D.; Quesada, M.; Woods, M. F.; Salzmann, T. N.
Christensen, B. G. Pure Appl. Chem. 1987, 59, 455.
(10) (a) Ernest, I.; Gosteli, J .; Greengrass, C. W.; Holick, W.;
J ackman, D. E.; Pfaendler, H. R.; Woodward, R. B. J . Am. Chem. Soc.
1978, 100, 8214. (b) Lang, M.; Prasad, K.; Hulick, W.; Gosteli, J .;
Ernest, I.; Woodward, R. B. J . Am. Chem. Soc. 1979, 101, 6296. (c)
Ernest, I.; Gosteli, J .; Woodward, R. B. J . Am. Chem. Soc. 1979, 101,
6301. (d) Pfaendler, H. R.; Gosteli, J .; Woodward, R. B. J . Am. Chem.
Soc. 1979, 101, 6306; (e) 1980, 102, 2039. (f) Franceschi, G.; Alpegiani,
M.; Battistini, C.; Bedeschi, A.; Perrone, E.; Zarini, F. Pure Appl. Chem.
1987, 59, 467.
(11) (a) Manhas, M. S.; Chib, J . S.; Chiang, Y. H.; Bose, A. K.
Tetrahedron 1969, 25, 4421. (b) Albers-Schonberg, G.; Arison, B. H.;
Hensens, T. O.; Hirshfield, K.; Hoogsteen, E.; Kaczka, A.; Rhodes, R.
E.; Kahan, J . S.; Ratcliffe, R. W.; Walton, E.; Ruswinkle, L. J .; Morin,
R. B.; Christensen, B. G. J . Am. Chem. Soc. 1978, 100, 6491. (c) Brown,
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A. J .; Howarth, T. T. J . Chem. Soc., Chem. Commun. 1979, 953. (e)
Menard, M.; Banville, J .; Martel, A.; Desiderio, J .; Fung-Tomc, J .;
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Chemistry: Cambridge, 1993; pp 3-20.
* Telephone: 813-974-7312. FAX:813-974-1733. email:eturos@chuma.
cas.usf.edu.
(1) Department of Chemistry, State University of New York at
Buffalo, Buffalo, NY 14260.
(2) On faculty leave from the Department of Chemistry, Tsinghua
University, Beijing, China 100084.
(3) Department of Biology, University of South Florida, Tampa, FL
33620.
(4) Departamento de Quimica Organica e Inorganica, Universidad
de Oviedo, 33071-Oviedo, Spain.
(5) Department of Chemistry, University of South Florida, Tampa,
FL 33620.
(6) (a) Chemistry and Biology of â-Lactam Antibiotics; Morin, R. B.,
Gorman, M., Eds.; Academic Press: New York, 1982, Vols. 1-3. (b)
Brown, A. G. Pure Appl. Chem. 1987, 59, 475.
(7) (a) The Chemistry of â-Lactams; Page, M. I., Ed.; Blackie
Academic and Professional: New York, 1996. (b) The Organic Chem-
istry of â-Lactams; Georg, G. I., Ed.; VCH: New York, 1993.
(8) For example, see: Huber, I.; Schneider, F. Helv. Chim. Acta 1994,
77, 1065.
10.1021/jo9811219 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/03/1998

Nonconventionally Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 63, No. 24, 1998 8899
acids,13 oxapenams,14 oxacephams,15 and monocyclic,16
spirocyclic,17 and multicyclic18 analogues. The most
common classes of â-lactam antibiotics are illustrated
below. Perhaps it is not coincidental that all biologically
active â-lactams, excluding the monocyclic compounds,
contain a fused ring framework having the lactam
nitrogen at the ring fusion, for it is the rigid conforma-
tional constraints and the highly pyramidalized nature
of the nitrogen center in these fused ring systems that
causes the lactam functionality to have diminished
planarity and resonance stabilization. Consequently, the
â-lactam ring within such structures has pronounced
reactivity toward nucleophilic attack and subsequent ring
opening.
systems whose lactam groups occupy “nonclassical” ori-
entations within the four-membered ring. Although a
handful of nonconventionally fused bicyclic â-lactams19
such as structures 1-8 have previously been described
in the literature, their chemical or biological properties
have not been investigated. In fact, the majority of these
compounds (1-7) have been utilized solely as intermedi-
ates in the synthesis of penicillins, carbapenems, and
cephalosporins. The structurally unusual N-fused â-lac-
tam derivative 8 was reported in 198020 as an unexpected
product obtained21 during an attempt to cyclize lactam
9 to penem 10 (Scheme 1).
To the best of our knowledge, there have not been any
efforts to evaluate the properties of fused â-lactam ring
(12) (a) Newton, G. G. F.; Abraham, E. P. Nature (London) 1955,
175, 548. (b) Abraham, E. P.; Newton, G. G. F. J . Biochem. 1961, 79,
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Bentley, P. H.; Brooks, G.; Gilpin, M. L.; Hunt, E. J . Chem. Soc., Chem.
Commun. 1977, 905. (c) Hunt, E.; Bentley, P. H.; Brooks, G.; Gilpin,
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Sch em e 1
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T.; Tsuji, T.; Kikkana, I.; Haga, N.; Satoh, H.; Itani, H.; Nagata, W. J .
Med. Chem. 1979, 22, 757. (b) Wolfe, S.; Ducep, J .-B.; Tin, K.-C.; Lee,
S.-L. Can. J . Chem. 1974, 52, 3996.
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Nature 1981, 289, 590. (b) Sykes, R. B.; Cimarusti, C. M.; Bonner, D.
P.; Bush, K.; Floyd, D. M.; Georgopapadakou, N. H.; Koster, W. H.;
Trejo, W. H.; Wells, J . S. Nature 1981, 291, 489. (c) Kamiya, T.;
Hashimoto, M.; Nakaguchi, O.; Oku, T. Tetrahedron 1979, 35, 323.
(d) Isaacs, N.; Sunman, G.; Reading, C. J . Antibiot. 1982, 35, 589. (e)
Kamiyama, T.; Aoki, H.; Mine, Y. In Chemistry and Biology of â-Lactam
Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic Press: New
York, 1982; Vol. 2, p 165. (f) Butler, A. R.; Robinson, D. I.; Wright, D.
E. J . Chem. Soc., Perkin Trans. 2 1982, 437. (g) Proctor, P.; Gansm-
antel, N.; Page, M. I. J . Chem. Soc., Perkin Trans. 2 1982, 1185. (h)
Sheehan, J . C.; Ryan, J . J . J . Am. Chem. Soc. 1951, 73, 1204.
(17) (a) Bateson, J . H.; Guest, A. W. Tetrahedron Lett. 1993, 34,
1799. (b) Le Blanc, S.; Pete, J .-P.; Piva, O. Tetrahedron Lett. 1992, 33,
1993. (c) Ishibashi, H.; Nakamura, N.; Sato, T.; Takeuchi, M.; Ikeda,
M. Tetrahedron Lett. 1991, 32, 1725. (d) Barrett, A. G. M.; Sturgess,
M. A. Tetrahedron 1988, 44, 5615. (e) Mullen, G. B.; St. Georgiev, V.
Heterocycles 1986, 24, 3441. (f) Ikeda, M.; Uchino, T.; Ishibashi, H.;
Tamura, Y.; Kido, M. J . Chem. Soc., Chem. Commun. 1984, 758. (g)
Spurr, P. R.; Hamon, D. P. G. J . Am. Chem. Soc. 1983, 105, 4734. (h)
Wittig, G.; Hesse, A. Liebigs Ann. Chem. 1976, 500.
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Gaviraghi, G. In Recent Advances in the Chemistry of Anti-Infective
Agents; Bentley, P. H., Ponsford, R., Eds.; The Royal Society of
Chemistry: Cambridge, 1993, pp 21-35. (b) Phillips, J . G.; Chu, D.;
Spanton, S.; Henry, R.; Plattner, J . J . Tetrahedron Lett. 1992, 33, 3733.
(c) Wollmann, T.; Gerlach, U.; Horlein, R.; Krass, N.; Lattrell, R.;
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Infective Agents; Bentley, P. H., Ponsford, R., Eds.; The Royal Society
of Chemistry: Cambridge, 1993, pp 50-66.
The purpose of our studies was to evaluate the proper-
ties of bicyclic â-lactam ring systems that have the lactam
(19) (a) Woodward, R. B.; Heusler, K.; Gosteli, J .; Naegeli, P.;
Oppolzer, W.; Ramage, R.; Ranganathan, S.; Vorbruggen, H. J . Am.
Chem. Soc. 1966, 88, 852. (b) Baldwin, J . E.; Christie, M. A.; Haber,
S. B.; Kruse, L. I. J . Am. Chem. Soc. 1976, 98, 3045. (c) Baldwin, J .
E.; Au, A.; Christie, M.; Haber, S. B.; Hesson, D. J . Am. Chem. Soc.
1975, 97, 5957. (d) Nakatsuka, S.-i.; Tanino, H.; Kishi, Y. J . Am. Chem.
Soc. 1975, 97, 5008. (e) Nakatsuka, S.-i.; Tanino, H.; Kishi, Y. J . Am.
Chem. Soc. 1975, 97, 5010. (f) Spitzer, W. A.; Goodson, T.; Lammert,
S. R.; Kukolja, S. J . Org. Chem. 1981, 46, 3568. (g) Cooper; R. D. G.;
J ose, F. L. J . Am. Chem. Soc. 1970, 92, 2576. (h) Barton, D. H. R.;
Comer, F.; Sammes, P. G. J . Am. Chem. Soc. 1969, 91, 1529. (i)
Natsugari, H.; Matsushita, Y.; Tamura, N.; Yoshioka, K.; Ochiai, M.
J . Chem. Soc., Perkin Trans. 1 1983, 403. In addition to these, some
intriguing studies on the design, synthesis, and reactivity of novel 10-
membered ring cyclic enediynes which possess a trans-fused â-lactam
ring as the triggering device for Bergmann cycloaromatization have
been described. (a) Banfi, L.; Guanti, G. Angew. Chem., Int. Ed. Engl.
1995, 34, 2393. (b) Banfi, L.; Basso, A.; Guanti, G. Tetrahedron. 1997,
53, 3249.
(20) Oida, S.; Yoshida, A.; Hayashi, T.; Nakayama E.; Sato, S.; Ohki,
E. Tetrahedron Lett. 1980, 21, 619.

8900 J . Org. Chem., Vol. 63, No. 24, 1998
Ren et al.
unit in different bonding arrangements compared to the
classical N-fused compounds. In considering the penam
ring system, for instance, three structural variants (desig-
nated types I, II, and III) can be conceived such that the
lactam functionality occupies alternative positions within
the bicyclic framework.
F igu r e 1. Effect of ring size on the infrared CdO absorption
frequency of N-fused versus C-fused bicyclic â-lactams.
binding proteins is essential. While it is not definitively
known whether the initial acylation step of â-lactam
hydrolysis in the â-lactamases is similar to that of the
penicillin binding proteins, both families of enzymes are
known to utilize an active site serine residue as the
nucleophilic catalyst and both lead to the formation of a
covalently attached acyl-enzyme intermediate.24 Here we
present the results of high-level ab initio calculations on
a general model for the base-catalyzed nucleophilic
addition of serine to a â-lactam. The model we have
employed is similar to the one reported recently by
Wladkowski25 and co-workers, who carried out the opti-
mization of the stationary points at the HF/6-31+G* level
of theory and evaluated the energy of these points at the
MP2/6-31+G*//6-31+G* level. However, in our experi-
ments we elected to optimize all the stationary points at
the higher MP2/6-31+G* level of theory, because the
correlation energy effects on the transition structures are
important. For our calculations, 2-azetidinone and 2-ami-
noethanol were used as models for the â-lactam substrate
and the nucleophilic serine residue, respectively, and two
molecules of NH3 were employed as models for the active
site lysine (acting as a general base) and alanine (which
electrophilically assists catalysis) residues.26 The geom-
etries of the stationary points found in these calculations
are shown in Figure 2. The point M is a minimum in
the potential energy surface and corresponds to the
starting complex in which the substrate is hydrogen-
bonded to the amino group of the serine model and to
the ammonia molecule simulating the alanine residue,
in good agreement with the experimental evidence de-
Since antibiotic activity among the â-lactams is, at
least qualitatively, dependent on the presence of a
reactive azetidinone ring, it was of interest to speculate
about the possible effects of positioning the lactam group
at other locations within the four-membered ring. Previ-
ous structural studies22 confirm that “N-fused” â-lactam
systems generally have a higher CdO stretching fre-
quency than the “C-fused” structures, indicating a greater
amount of ring strain and chemical reactivity toward
nucleophiles. N-Fused lactams are highly respondent to
the geometric constraints imposed by the second ring to
which it is fused, as evidenced from the increase in the
infrared absorption frequency for the lactam carbonyl as
the size of the second ring is decreased (Figure 1). For
C-fused rings, the size of the appended ring has little if
any influence on the frequency of CdO absorption. This
suggests a fundamental and potentially exploitable dif-
ference between N-fused and C-fused â-lactam rings.23
Resu lts a n d Discu ssion
Com p u ta tion a l Stu d ies. AM1 semiempirical calcu-
lations were carried out on each of the four isomeric
penam rings to gain further insight into their relative
stabilities. In the calculations, a methyl group was
placed on the â-lactam ring to preserve the tertiary na-
ture of the lactam nitrogen, and the carboxylic acid group
on the sulfur ring was omitted to avoid computational
discrepancies due to hydrogen-bonding effects. Interest-
ingly, these calculations suggest that all three of the
isopenams have nearly the same thermodynamic stability
as the classical penam ring system, based on their calcu-
lated gas phase heats of formation (Table 1). Whereas
our type I and III penam analogues are of equal stability
to the parent penam, the type II structure is about 1.4
kcal/mol thermodynamically more stable. Similar results
were observed in our calculations within the penem series
of structures shown at the bottom of Table 1.
(23) Although early investigations indicated that the more active
â-lactam antibiotics tend to have a shorter CdO bond and a more
highly pyramidalized nitrogen center than the biologically inactive
analogues, it has since been realized that a clear relationship between
the electrophilicity or reactivity of a given â-lactam compound and its
biological effectiveness does not necessarily exist. Enzyme binding
(active site fit), hydrolytic stability and solubility, ring fragmentation
pathways, and degradation properties are factors which determine a
â-lactam’s therapeutic efficacy. For some lead references and discus-
sions, see: Blaszczak, L. C.; Brown, R. F.; Cook, G. K.; Hornback, W.
J .; Hoying, R. C.; Indelicato, J . M.; J ordon, C. L.; Katner, A. S.; Kinnick,
M. D.; McDonald, J . H., III.; Morin, J . M., J r.; Munroe, J . E.; Pasini,
C. E. J . Med. Chem. 1990, 33, 1656.
To relate the reactivity and stability of a â-lactam
compound to its antibacterial properties, a detailed
knowledge of the catalytic mechanism of the penicillin
(21) DeNinno, F.; Linek, E. V.; Christensen, B. C. J . Am. Chem. Soc.
1979, 101, 2210.
(22) (a) Sweet, R. M. In Cephalosporins and Penicillins, Chemistry
and Biology; Flynn, E. H., Ed.; 1972, p 280. (b) Dunn, G. L. In
Comprehensive Heterocyclic Chemistry; Lwowski, W., Ed.; Pergamon
Press: New York, 1984; Vol. 7, pp 341-363.
(24) Knox, J . R.; Moews, P. C.; Frere, J .-M. Chem. Biol. 1996, 3,
937.
(25) Wladkowski, B. D.; Chenoweth, S. A.; Sanders, J . N.; Krauss,
M.; Stevens, W. J . J . Am. Chem. Soc. 1997, 119, 6423.
(26) Strynadka, N. C.; Adachi, H.; J ensen, S. E.; J ohns, K.; Sielecki,
A.; Betzel, C.; Sutoh, K.; J ames, M. N. Nature 1992, 359, 700.

Nonconventionally Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 63, No. 24, 1998 8901
Ta ble 1. Ca lcu la ted Ga s P h a se Hea ts of F or m a tion of Bicyclic â-La cta m Rin gs (k ca l/m ol)
which reveals a significant amount of charge (0.302
electrons) being transferred from the oxygen of the
approaching serine nucleophile to the â-lactam carbonyl.
This suggests that the addition of the catalytic serine to
a â-lactam substrate within the active site is largely
controlled by the interaction between the HOMO of the
nucleophile (serine) and the LUMO of the electrophile
(â-lactam). Thus, within a series of closely related
â-lactam structures, the LUMO energy of the â-lactam
can be a direct indicator of the compound’s reactivity
toward nucleophilic ring opening in the enzyme active
site, providing that the geometry and binding parameters
are not significantly perturbed.
Therefore, we thought it would be informative to
calculate the LUMO energies of the four isomeric penem
rings 11-14. This was done at the HF/6-31G* level of
theory. The optimized geometries obtained for these
structures are shown in Figure 3, and their computed
LUMO energy values are listed in Table 2. The main
difference between the four isomers is in the degree of
twisting within the â-lactam ring, as reflected by the
N-C1-C2-C3 dihedral angle D. For 2-azetidinone, the
four centers of the ring all lie within a common plane.
The C-fused lactams 11 and 12, however, are slightly
twisted out of planarity by 2-3°, and the N-fused rings
13 and 14 are contorted to an even greater extent.
Another key structural difference between the four
isomers is that the lactam nitrogen centers in 11 and in
12 are planar, while in 13 and 14 they are distinctly
pyramidalized.
The calculated values of the LUMO energies for
optimized structures 11-14 indicate that the electrophi-
licity of both C-fused bicyclic â-lactams (11 and 12) is
significantly greater than that of 2-azetidinone but lower
than that of the two N-fused bicyclic analogues (13 and
14). In comparing the two N-fused lactams 13 and 14,
the N-S fused isomer 14 has a somewhat lower LUMO
energy value than the classical penem 13. Thus, having
a lactam-fused ring structure diminishes the LUMO
energies and increases the electrophilicity of the â-lactam
ring. One would then predict that the reactivity of these
â-lactam rings toward nucleophilic addition would follow
the trend 11 < 12 < 13 < 14, despite the similarity of
their thermodynamic stabilities.
F igu r e 2. MP2/6-31+G* optimized geometries of the starting
complex (M) and the transition structure (TS) for the catalyzed
hydrolysis of 2-azetidinone (bond lengths are in angstroms).
rived from crystallographic studies.27 The point TS is the
transition structure for the formation of the tetrahedral
intermediate during the â-lactam hydrolysis. In this
transition structure, the distance between the oxygen of
the serine and the carbonyl center of the â-lactam has
been reduced to 1.857 Å, and the O-C-O angle is almost
perfectly tetrahedral (110°). In addition, the distance
between the hydrogen of the serine hydroxyl group and
the lysine amino group is now only 1.177 Å, while the
O-H distance has increased to 1.342 Å. Each of these
changes reflect that the nucleophilic attack of the serine
hydroxyl group to the â-lactam carbonyl is concerted,
with hydrogen transfer taking place from the serine
hydroxyl group to the nitrogen atom of the lysine residue.
An interesting feature of the transition structure TS is
the considerable degree of pyramidalization at the lactam
nitrogen center, which now exhibits nearly sp3 hybridiza-
tion. It is interesting to relate this to the fact that most
of the biologically active â-lactams are bicyclic and have
the lactam nitrogen in an sp3 hybridization state. Ac-
cording to the data from these MP2/6-31+G* calculations,
the activation energy for the nucleophilic attack of the
serine on 2-azetidinone is predicted to be 23.0 kcal mol-1
,
which is slightly lower than the value obtained previously
using a closely related model.23 An important outcome
of this computational experiment comes from the analysis
of the Mulliken charges in the transition structure TS,
Syn th etic Stu d ies. To construct the functionalized
cores of our isomeric â-lactam structures, we developed
a concise “double annulation” strategy shown in eq 1. In
the first step of this procedure, the â-lactam ring is
(27) (a) Staudinger, M. Liebigs Ann. Chem. 1907, 356, 51. (b) Georg,
G. I.; Ravikumar, V. T. In The Organic Chemistry of â-Lactams, Georg,
G. I., Ed.; Verlag Chemie: New York, 1993; pp 295-368. (c) Sandhn,
J . S.; Sain, B. Heterocycles 1987, 26, 777.

8902 J . Org. Chem., Vol. 63, No. 24, 1998
Ren et al.
Ta ble 2. Com p a r ison of th e En er gies of th e Low est
Un occu p ied Molecu la r Or bita l (LUMO) for 2-Azetid in on e
a n d â-La cta m s 11-14
argylic imine 16 in the presence of a stoichiometric
amount of Et3N. Cycloadducts 17 were obtained as a 10:1
mixture of stereoisomers in 88% yield. Unfortunately,
the predominant adduct in this crude composition was
the undesired trans isomer, in contrast to the normally
cis-selective [2 + 2]-cycloadditions of imines with R-alkoxy-
and R-aminoacetyl chlorides.32 Efforts to improve the
cis-selectivity of these reactions by varying the reac-
tion conditions or workup procedure were unsuccessful.
However, the conversion of this mixture to a more
favorable 1:2 cis:trans composition could be carried out
by treating the unpurified â-lactam products with n-
butyllithium at -78 °C followed by aqueous acetic acid.
While the diastereomers of 17 could be separated by flash
column chromatography, it was more convenient to
simply carry the mixture on to the halogenation step, at
which point the unreacted trans isomer could be easily
retrieved. The halocyclization reaction of cis-17 was
effected using 1 equiv of I2 in CH2Cl2 at room tempera-
ture, affording bicycloadduct 18 in better than 95% yield
(based on the recovered amount of trans-17). From our
previous studies on iodocyclization reactions of 3-butynyl
benzyl sulfides, we ascertained that 5-endo cyclization
F igu r e 3. HF/6-31G* optimized geometries of 2-azetidinone
and penems 11-14 (italicized bond lengths are in angstroms,
and D is the N-C1-C2-C3 dihedral angle).
formed by a classical Staudinger reaction28 between an
R-(alkylthio)ketene equivalent and an R,â-unsaturated
imine. The sulfur ring is subsequently closed onto the
â-lactam unit by a halogen-promoted heterocyclization
process.29 The minimal number of steps required to
access various types of [3.2.0]ring systems, and the
opportunity to vary ring substituents R1, R2, R3, and X,
are attractive features of this methodology.30
(29) [2 + 2]-cycloadditions of R-arylthioacetyl chlorides with imines
have been reported previously. (a) Palomo, C.; Cossio, F. P.; Odiozola,
J . M.; Oiarbide, M.; Ontoria, J . M. Tetrahedron Lett. 1989, 30, 4577.
(b) Palomo, C.; Cossio, F. P.; Odiozola, J . M.; Oiarbide, M.; Ontoria, J .
M. J . Org. Chem. 1991, 56, 4418. (c) Ishida, M.; Minami, T.; Agawa,
T. J . Org. Chem. 1979, 44, 2069.
(30) This halocyclization procedure is somewhat reminiscent of the
classical Morin isomerization of penicillin sulfoxides to cephams, a
process thought to occur via intramolecular addition of an electrophilic
sulfur group to an olefin. (Morin, R. B.; J ackson, B. G.; Mueller, R. A.;
Lavagnino, E. R.; Scanlon, W. B.; Andrews, S. L. J . Am. Chem. Soc.
1963, 85, 1896.) For discussions and references, see: (a) Cooper, R. D.
G.; Hatfield, L. D.; Spry, D. O. Acc. Chem. Res. 1973, 6, 32. (b)
Chemistry and Biology of â-Lactam Antibiotics; Morin, R. B., Gorman,
M., Eds.; Academic Press: New York, 1982; Vol. I. For related
methodology involving an intramolecular sulfenylation of an allene,
see: Farina, V.; Kant, J . Tetrahedron Lett. 1992, 33, 3559.
(31) This acid chloride can be easily prepared from the commercially
available carboxylic acid by refluxing in thionyl chloride.
Implementation of this strategy was first applied to
the synthesis of type I penem 18, as illustrated in Scheme
2. The sequence begins with treatment of an equimolar
mixture of S-benzylthioacetyl chloride31 (15) with prop-
(28) (a) Ren, X.-F.; Turos, E. Tetrahedron Lett. 1993, 1575. (b) Ren,
X.-F.; Turos, E.; Lake, C. H.; Churchill, M. R. J . Org. Chem. 1995, 60,
6468.
(32) For examples and discussions on the synthesis of R-alkoxy- and
R-amino-substituted â-lactams, refer to ref 7b, Chapter 6, pp 295-
368.

Nonconventionally Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 63, No. 24, 1998 8903
Sch em e 2
Sch em e 3
products are formed exclusively over the 4-exo adducts,
because of the significantly greater ring strain associated
with forming the four- versus the five-membered sulfur
ring.28
the one producing the â-bromo isomer via transition state
B*, for several reasons. First, the A1,3-type interactions
of the vinyl methyl with the hydrogen at the ring fusion
in A* should be more severe than the corresponding A1,2
-
Using an analogous procedure, alkenyl â-lactams 20
were prepared from acid chloride 15 and the N-(4-
methoxyphenyl)imine 19 of 3-methyl-2-butenal (Scheme
3). In this case, treatment of the initial product mixture
according to the above-described deprotonation/protona-
tion procedure gave a 1:3 mixture of cis:trans diastere-
omers in 77% overall combined yield. In the imine-acid
chloride coupling reaction, an unidentified isomeric, non-
â-lactam containing byproduct33 was also obtained in
amounts that varied depending on reaction and workup
conditions. Bromination of the 1:3 mixture of alkenyl
sulfides 20 with 1 molar equiv of Br2 in CH2Cl2 solution
led to the isolation of 21 (90% based on cis-20) as a 1:5
mixture of R:â bromo epimers, as well as products arising
from bromination of the olefin centers in trans-20 (eq 2).
Assignment of relative stereochemistry in adducts 21 is
based on comparison of the magnitude of the vicinal
coupling constants for the proton at the brominated
center in R-bromo (J ) 4.0 Hz) and â-bromo (J ) 5.2 Hz)
compounds 21 with their Dreiding models.
type interactions between the vinyl hydrogen and hy-
drogen at the ring fusion in B*. Second, ring closure
through B* is geometrically better suited with respect
to the positioning of sulfur’s nonbonding electron pairs34
for attack at the terminus of the double bond.
We were interested in synthesizing â-lactams such as
25 that bear a large alkylthio substituent at the R-carbon.
Heterosubstitution at the center R to the carbonyl on a
â-lactam ring can often enhance the electrophilic proper-
ties and hydrolytic stability of the lactam carbonyl.35 We
envisioned that compounds 25 could best be accessed by
(33) We speculate that this isomeric material may be
2]-cycloadduct that forms between the crotonimine and ketene, al-
though no attempt was made to confirm this structure.
a [4 +
(34) Preliminary accounts of this research have been communicated
in the following articles: (a) Ren, X.-F.; Turos, E. J . Org. Chem. 1994,
59, 5858. (b) Ren, X.-F.; Konaklieva, M. I.; Turos, E. J . Org. Chem.
1995, 60, 4980. (c) Konaklieva, I.; Shi, H.; Turos, E. Tetrahedron Lett.
1997, 38, 8647. Also, refer to ref 28b.
(35) For instance, 7R-methoxylation of the cephalosporin ring system
markedly enhances â-lactamase resistance. (a) Strominger, J . L.;
Tipper, D. J . Am. J . Med. 1965, 39, 707. (b) Cama, L. D.; Leanza, W.
J .; Beattie, T. R.; Christensen, B. G. J . Am. Chem. Soc. 1972, 94, 1408.
(c) Stapley, E. O.; Birnbaum, J .; Miller, A. K.; Wallick, H.; Hendlin,
D.; Woodruff, H. B. Rev. Inf. Dis. 1979, 1, 73 and references therein.
(d) Nagarajan, R.; Boeck, L. D.; Gorman, M.; Hamill, R. L.; Higgens,
C. E.; Hoehn, M. M.; Stark, W. M.; Whitney, J . G. J . Am. Chem. Soc.
1971, 93, 2308. However, heterosubstitution on the penicillin core
generally diminishes antibiotic activity (Bentley, P. H.; Clayton, J . P.
In Recent Advances in the Chemistry of â-Lactam Antibiotics; Elks, J .,
Ed.; Special Publication No. 28, The Chemical Society: London, 1977;
pp 68-72), although the penicillin derivative temocillin seems to be
an exception (Slocombe, B.; Basker, M. J .; Bentley, P. H.; Clayton, J .
P.; Cole, M.; Comber, K. R.; Dixon, R. A.; Edmondson, R. A.; J ackson,
D.; Merrikin, D. J .; Sutherland, R. Antimicrob. Agents Chemother.
1981, 20, 38).
Figure 4 shows two possible pathways for halocycliza-
tion of cis-20. Ring closure leading to the R-bromo
product via transition state A* should be disfavored over

8904 J . Org. Chem., Vol. 63, No. 24, 1998
Ren et al.
F igu r e 4. Comparison of geometries for the halocyclization of cis-20.
halocyclization of acetylenic dithiane 24, which could be
readily prepared from acid chloride 22 and imine 23
following the published method36 of Sharma (eq 3).
halocyclization procedure (Scheme 4). Dithianes 30 were
prepared from [2 + 2]-coupling of bis(ethylthio)acetyl
chloride37 (28) and propargyl imines 29 and subsequently
subjected to iodination using 1 molar equiv of I2. Excel-
lent yields of the desired bicycloadducts 31 were produced
upon workup of the reaction. R-Thiosubstituted penam
analogues 34 were similarly synthesized in two steps,
starting from the condensation of acid chloride 28 and
N-benzylimine 32. Obtained from this reaction was
â-lactam 33 in 58% yield, which upon bromination38
afforded isopenicillin derivative 34 as a 1:4 mixture of
R: â Br epimers. Relative stereochemical assignments for
34 are in accord with those made previously for â-lactam
21. The conversion of 30 to 31 and 33 to 34 represents,
to the best of our knowledge, the first examples of a
halocyclization reaction in which a thioketal serves as
the nucleophilic component.
Our attention next turned to the synthesis of “inversely
fused” penem and clavulanic acid analogues illustrated
in Figure 5. The four boxed structures represent the
formal hybridization of the penem/clavulanic acid ring
systems with that of the monobactams, an intriguing
class of monocyclic â-lactams whose potent antibacterial
properties have been attributed to the strongly electron-
withdrawing N-sulfato group.39 In these hybridized ring
structures, the â-lactam nitrogen is both at the ring
fusion and directly bonded to sulfur, in an unusual
bonding arrangement found only in one previously re-
ported structure (see compound 8).
Unfortunately, attempts to effect the halocyclization of
spiro dithiane 24 were unsuccessful. The resistance of
this substrate to undergo cyclization to 25 may be due
to difficulty in forming tricyclic intermediate 27, or in
effecting its subsequent ring opening (eq 4).
Penem analogues 39, whose interesting heterocyclic
array contains five heteroatom-bearing ring carbons,
were synthesized according to the procedure devised in
Scheme 5. The requisite cis-alkenyl azetidinones 36 were
(37) The synthesis of 3-bis(ethylthio)azetidinones has been reported
previously. Cossio, F. P.; Ganboa, I.; Garcia, J . M.; Lecea, B.; Palomo,
C. Tetrahedron Lett. 1987, 28, 1945. Also see: Abramski, W.; Belzecki,
C.; Chielewski, M. Bull. Pol. Acad. Sci. Chem. 1985, 33, 451.
(38) In the bromination reaction of 33, a small amount of the proto
derivative (shown below) can also be obtained, presumably from HBr-
promoted ring closure.
In an attempt to circumvent this problem, an alterna-
tive route to R-thiosubstituted â-lactams was explored
using bis(thioether) â-lactams 30 as substrates for the
(39) (a) Slusarchyk, W. A.; Dejneka, T.; Gordon, E. M.; Weaver, E.
R.; Koster, W. H. Heterocycles 1984, 21, 191. (b) Cimarusti, C. M.;
Sykes, R. B. Med. Res. Rev. 1984, 4, 1.
(36) Sharma, S. D.; Mehra, U.; Khurana, J . P. S.; Pandhi, S. B.
Synthesis 1987, 990.

Nonconventionally Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 63, No. 24, 1998 8905
F igu r e 5. Novel penem-monobactam and clavulanic acid-monobactam hybrids.
Sch em e 4
Sch em e 5
spectra, which showed characteristic doublets for the two
ring protons with vicinal coupling constants of 4.8 Hz.40
The aryl nitrogen protecting group of 36 was removed
by oxidation with ceric ammonium nitrate41 to give 37.
Deprotonation of 37 with n-BuLi at low temperature and
subsequent trapping of the amide anion with methyl
methanethiosulfonate42 afforded N-(methylthio)-substi-
tuted â-lactams 38 in high overall yield.
In contemplating the possibility of forming isopenem
ring system 39 via halogenation of substrate 38, we
realized that the use of an N-acylsulfenamide as a
nucleophile in halocyclizations onto unsaturated centers
is an unprecedented reaction. We had initial concerns
that the lactam group might discourage ring closure by
electronically deactivating the sulfur toward nucleophilic
addition onto the π-system, or by introducing additional
geometric constraints that could potentially interfere
with the cyclization process. Despite these concerns, the
cyclization of 38 proceeded cleanly using I2 in dichlo-
romethane to give 39 as a single bicyclic â-lactam having
a CdO stretching band near 1790 cm-1
. The fact,
(40) Cis-disubstituted â-lactams characteristically show a vicinal
coupling constant of 4.8-6.0 Hz, while for trans-disubstituted â-lac-
tams this value is typically only 1-3 Hz.
prepared in about 90% yield by condensation of meth-
oxyacetyl chloride (35a ) or N-phthalimidoacetyl chloride
(35b) with N-arylamine 16. The cis relative stereochem-
istry of these adducts was evident from the 1H NMR
(41) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J . Org. Chem. 1982,
47, 2765.
(42) Shah, N. V.; Cama, L. D. Heterocycles 1987, 25, 221.

8906 J . Org. Chem., Vol. 63, No. 24, 1998
Ren et al.
F igu r e 6. Nitrogen inversion in â-lactams 38.
F igu r e 7. Sulfur-nitrogen bond rotation in â-lactams 38.
F igu r e 8. Sulfur-nitrogen bond rotation in thiamazins.
however, that the ring closure proceeded sluggishly over
several hours at an elevated temperature (40 °C) sup-
ports our initial speculation that N-acyl sulfenamide
systems would be less prone to halocyclization than the
corresponding thioether analogues (see 30 in Scheme 4),
which halocyclize readily at room temperature. There
are several likely reasons for this. First, the product of
the reaction, N-fused lactam 39, is conformationally more
constrained than the corresponding C-fused analogues
31 formed in the thioether ring closures. Thus, the loss
of amide resonance associated with increasing pyrami-
dalization of the nitrogen center would discourage forma-
tion of the N-fused bicyclic lactam. Moreover, electron
withdrawal by the N-acyl group of 38 would diminish
nucleophilicity at sulfur. It is also conceivable that sulfur
can slow the rate of configurational inversion at the nitro-
gen center (assuming some residual sp3 character), estab-
lishing an equilibrium that favors the trans invertomer
over the cis form required for cyclization (Figure 6), or
that restricted isomerization around the N-S bond of 38
could orient sulfur’s nonbonding orbitals away from the
triple bond (see conformer 2 in Figure 7). Sulfenamides
can have significant barriers to rotation around the
sulfur-nitrogen single bond, generally in the range of
9-23 kcal/mol.43 Miller and his colleagues have observed
this behavior in their studies on the closely related
thiamazin â-lactams, whose barrier to sulfur-nitrogen
bond rotation was determined to be as high as 12 kcal/
mol (Figure 8).44 In examining the behavior of our
â-lactams by variable temperature NMR, however, we
found that lactams 38 exist as single compounds over a
temperature range of -50 to +50 °C, which suggests that
neither of the latter two isomerization phenomena is a
factor in the cyclizations of our N-SMe â-lactams. Rather,
the slow rate for halocyclization of these sulfenamides
compared to the corresponding thioethers is most likely
due to electron withdrawal by the N-acyl moiety and
unfavorable geometric or stereoelectronic demands.
The difference in reactivity between the latter two
â-lactam systems is also revealed in the ring-closing
reactions of thioether lactam 33 and sulfenamide lactams
40 and 41. Whereas alkenyl thioether 33 undergoes facile
5-endo-trig cyclization upon reaction with bromine to
provide bicyclic â-lactam 34 (refer to Scheme 4), alkenyl
sulfenamides 40 and 41 fail to give the desired cyclization
products 42 (eq 5). This would seem to indicate that the
geometric/stereoelectronic constraints within 40 and 41
are even more prohibitive than those in the acetylenic
substrates 38, with the intramolecular addition of sulfur
to the double bond now being energetically unfavorable.
Consequently, diastereomeric mixtures of olefin bromi-
nation products 43 and 44 are instead produced from
these halogenation reactions (eq 6).45 Efforts to convert
the unwanted dibrominated adducts 43 and 44 to het-
erocycles 42 under a variety of thermolytic conditions
were unproductive.
The necessity of having the two reactive groups in-
volved in the halocyclization, the sulfur and unsaturated
(44) (a) Woulfe, S. R.; Miller, M. J . J . Med. Chem. 1985, 28, 1447.
(b) Woulfe, S. R.; Miller, M. J . J . Org. Chem. 1986, 51, 3133. (c) Boyd,
D. B.; Eigenbrot, C.; Indelicato, J . M.; Miller, M. J .; Pasini, C. E.;
Woulfe, S. R. J . Med. Chem. 1987, 30, 528. In this paper, the authors
report that approximately 50% of the thiamazin undergoes decomposi-
tion at pH 11 by cleavage of the nitrogen-sulfur bond, at a rate of
0.35 h-1. This process occurs through hydroxide ion attack on the sulfur
center as well as via deprotonation of the SCH2CO2R group.
(43) Raban, M. Tetrahedron 1984, 40, 3345.

Nonconventionally Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 63, No. 24, 1998 8907
Sch em e 6
5-exo-dig ring closure, adducts 53 have been assigned to
have an exocyclic olefin with the E geometry arising from
stereospecific trans addition to the triple bond. The
relative configuration of the allylic acetate center in 53
is of particular interest, since it originates from a
stereoselective addition of acetylide anion to chiral alde-
hydes 49. The stereochemistry of this nucleophilic ad-
dition can be rationalized using the Felkin-Anh47 model,
as illustrated in Figure 9. In this conformation having
the electron-withdrawing nitrogen of the â-lactam ring
orthogonal to the carbonyl group, attack of the lithium
acetylide anion would occur more readily from the less
congested R-face of the aldehyde, leading to alcohol 54.
In the case of methoxy-substituted aldehyde 49a , the
ratio of R:â acetate products can be inverted by conduct-
ing the acetylide addition reaction in the presence of a
stoichiometric amount of MgCl2. We speculate that in
this case the addition occurs preferentially by approach
of the acetylide from the less hindered face of a chelated
magnesium complex, with the metal ion coordinating the
oxygens of the methoxy and aldehyde moieties, to give
alcohol 55 (Figure 10).
From the infrared spectra of â-lactams 53, it is readily
apparent that the lactam carbonyl is electrophically
enhanced by the lactam nitrogen being both at the site
of ring fusion and bonded to the electronegative sulfur
atom. The stretching absorption frequency for the car-
bonyl in these analogues appears at a considerably higher
wavenumber (υCdO 1780 cm-1) than that observed for the
C-fused analogues 31 and 34 (υCdO 1750-1760 cm-1) and
is within the same range as the biologically active penems
(υCdO 1775-1785 cm-1). Despite their unusually high
electrophilicities, these N-S-fused lactams appear to be
quite resistant toward hydrolytic conditions and can be
easily isolated from aqueous sodium bisulfite solution and
purified by silica gel flash chromatography without any
apparent decomposition. They tolerate prolonged expo-
sure to aqueous media ranging from pH 4 to 10 and are
thus comparable to the monocyclic thiamazins that have
been reported by Miller to be hydrolytically stable below
pH 11.44
ring substituents, cis on the â-lactam ring suggests the
possibility of being able to direct the cis and trans â-lac-
tam isomers to regioisomeric ring adducts. For example,
the iodocyclization shown previously in Scheme 2 involv-
ing a cis/trans mixture of â-lactams 17 led to cyclization
of only the cis compound, producing the C-fused bicy-
cloadduct 18. With the recovered trans isomer from this
reaction, we were able to prepare the N-methylthio
â-lactam 46. Iodination of 46 in refluxing CH2Cl2 solu-
tion provided the N-fused ring compound 47 (Scheme 6).
We intended to utilize a similar halocyclization protocol
for the synthesis of clavulanic acid analogues 53 (Scheme
7). The requisite â-lactam starting materials 48 were
obtained by reaction of acetyl chlorides 35a or 35b with
crotonaldehyde imine in the presence of a stoichiometric
amount of triethylamine at 0 °C. The cis stereochemistry
1
of adducts 48 was assigned on the basis of a H NMR J
coupling value of 4.8 Hz for the two protons on the
â-lactam ring. Ozonolysis of 48 at room temperature
provided cis aldehydes 49 in high yield without any
detectible epimerization. To incorporate the required
acetylenic side chain onto the â-lactam ring of intermedi-
ate 50, an acetylide anion addition to aldehyde precursor
49 was carried out. Addition of lithium phenylacetylide
to 49 proceeded stereoselectively to give the alcohol
adducts, which afforded acetates 50 upon acetylation
under standard conditions. Compound 50a was isolated
as a 1:5 mixture of R:â stereoisomers in 55% combined
yield after flash chromatography, while 50b was obtained
in 69% overall yield as a 1:2 mixture of R:â diastereomers.
Deprotection of the N-methoxyphenyl group of 50 and
installment of the methylthio moiety onto the lactam
nitrogen proceeded smoothly. The minor stereoisomers
of 52 could be chromatographically separated at this
juncture. Iodocyclization of 52a and 52b was effected
with I2 in CH2Cl2 at room temperature to give 53a and
53b, respectively, in high yield. These bicycloadducts are
unusual in that they contain six contiguous and uniquely
heterosubstituted carbon centers within their backbone.
In light of our previous studies46 which demonstrated the
overwhelming preference of alkynyl sulfides to undergo
Listed in Table 3 are the carbonyl stretching frequen-
cies recorded for the various bicyclic â-lactam derivatives
from our study. Comparison of the observed carbonyl
infrared absorption frequencies indicates that the simple
C-fused penem and penam analogues 31 and 34 (υCdO
1750-1760 cm-1) are somewhat less electrophilic than
the parent antibiotics (υCdO 1775-1785 cm-1), which is
in agreement with earlier studies which show that
N-fused â-lactams absorb at about 15 cm-1 higher than
the C-fused rings (vide supra). Since biological activity
of â-lactam antibiotics is attributable to a highly elec-
trophilic carbonyl carbon, we thought that the electro-
philicity of these compounds could be enhanced through
oxidation of the sulfur atom(s).48 This was demonstrated
by converting â-lactams 31 and 34 to their disulfone
(47) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett.
1968, 9, 2199. (b) Anh, N. T.; Eisenstein, O. Nouv. J . Chem. 1977, 1,
61.
(45) The proton NMR spectra of the adducts 43 and 44 from
bromination of trans-40 and trans-41 shows the retention of the
azetidinyl S-Me groups (appearing as separate singlets for the two
diastereomers).
(46) For more detailed discussions on stereoelectronic requirements
in sulfur halocyclizations, see the papers cited in ref 28 as well as the
following article on related cyclization chemistry. Ren, X.-F.; Konak-
lieva, M. I.; Turos, E.; Krajkowski, L. M.; Lake, C. H.; J anik, T. S.;
Churchill, M. R. J . Org. Chem. 1995, 60, 6484.
(48) Oxidation of penicillins and cephalosporins to their sulfoxides
and sulfones increases the â-lactam carbonyl stretching frequency by
15 and 45 cm-1, respectively. (See: Demarco, P. V.; Nagarajan, R. In
Cephalosporins and Penicillins: Chemistry and Biology; Flynn, E.
H., Ed., Academic Press: New York, 1972; pp 315-320). Penicillin
sulfones lack antibiotic activity but show â-lactamase inhibition.
(For insight into their mechanism of action and lead references, see:
Fink, A. L.; Ellerby, L. M.; Bassett, P. M. J . Am. Chem. Soc. 1989,
111, 6871).

8908 J . Org. Chem., Vol. 63, No. 24, 1998
Ren et al.
Sch em e 7
derivatives 56 and 57, respectively, using m-chloroper-
oxybenzoic acid (mCPBA)49 in CH2Cl2 solution buffered
with Na2HPO4-NaH2PO4 (eqs 7 and 8). As anticipated,
the electron-withdrawing influence of the twin R-disul-
fone groups on the lactam carbonyl can be observed by
the shift in the infrared absorption frequency for the
experiments. Since all “conventional” penicillin antibiot-
ics and â-lactamase inhibitors contain an ionizable
group50 (such as a carboxylic acid) on the thiazolidine
CdO bond from 1750-1760 cm-1 (for sulfides 31 and 34)
to 1775-1785 cm-1 (for disulfones 56 and 57). Similarly,
peracid oxidation of sulfenamides 39 afforded sulfona-
mides 58 whose infrared absorption band near 1800 cm-1
confirms both the survival of the â-lactam ring during
the oxidation and workup procedures and the unusually
short CdO bond (eq 9). These highly electrophilic bicyclic
disulfone and sulfonamide derivatives are stable to
aqueous NaHSO3 and NaHCO3 workup conditions and
to silica gel chromatography and show no tendency to
hydrolyze under neutral or mildly basic conditions.
F igu r e 9. Stereochemistry of lithium acetylide addition to
49.
F igu r e 10. Stereochemistry of lithium acetylide addition to
49a in the presence of MgCl2.
F u n ction a liza tion of â-La cta m Cor e Str u ctu r es.
With a selection of new â-lactam core structures available
to us, our attention turned to the preparation of deriva-
tized compounds for preliminary antimicrobial testing
ring, it seemed desirable to begin these investigations
by studying methods for derivatizing some of our â-lac-
tam core structures with more polar, and possibly ioniz-
able, functionality. In considering the various options
for modifying our â-lactam rings, we felt that the halogen
(49) (a) Cooper, R. D. G.; DeMarco, P. V.; Cheng, J . C.; J ones, N. D.
J . Am. Chem. Soc. 1969, 91, 1408. (b) Cooper, R. D. G.; DeMarco, P.
V.; Spry, D. O. J . Am. Chem. Soc. 1969, 91, 1528.

Nonconventionally Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 63, No. 24, 1998 8909
Ta ble 3. In fr a r ed CdO Str etch in g F r equ en cy for â-La cta m s
Sch em e 8
could serve as the most direct means to introduce other
we attempted to selectively reduce off the benzyl thio-
carbonate moiety to release the free thiol, with the expec-
tation that cyclization of 65 to give 66 would occur spon-
taneously upon aerobic workup (Scheme 10). However,
the only product observed by proton NMR to form upon
catalytic hydrogenation of 64 was Z-olefin 67, resulting
from partial reduction of the triple bond side chain.
functionality via a metal-halogen exchange and reaction
with a suitable electrophile (Scheme 8). However, it soon
became apparent that this would be more difficult than
first envisioned, due to the fact that the halide in these
C-fused penems is both â to and antiperiplanar to a sulfur
leaving group.
Our initial attempts to carry out low-temperature
metalation reactions on 59 using tBuLi or Mg°, with
subsequent alkylation or aldol reaction, led only to
products 62 derived from opening of the dihydrothiophene
or â-lactam rings. The reaction shown in Scheme 9
illustrates one unsuccessful attempt to esterify iodide 31b
by lithiation and trapping with benzyl chloroformate,
which results instead in the formation of ring-opened
adduct 64 by â-elimination. In an effort to revert this
unwanted material back to a bicyclic derivative of 31b,
Sch em e 9
(50) (a) Imtiaz, U.; Billings, E.; Knox, J . R.; Manavathu, E. K.;
Lerner, S. A.; Mobashery, S. J . Am. Chem. Soc. 1993, 115, 4435. (b)
Knox, J . R.; Moews, P. C. J . Mol. Biol. 1991, 220, 435. (c) Moews, P.
C.; Knox, J . R.; Dideberg, O.; Charlier, P.; Frere, J . M. Proteins 1990,
7, 156. (d) Herzberg, O.; Moult, J . Science 1987, 236, 694.

8910 J . Org. Chem., Vol. 63, No. 24, 1998
Ren et al.
Sch em e 10
Similar efforts to generate and trap a vinyl radical
intermediate from â-lactam 31b also failed to provide the
desired substitution products. For instance, upon reac-
tion of vinyl iodide 31b with Bu3SnH/AIBN or (Bu3Sn)2
in the presence of various radical trapping agents, only
disulfide product 69 was obtained instead of the olefin
addition product 68. The dimeric structure of 69 was
confirmed by mass spectrometry. This product undoubt-
edly arises from a rapid elimination51 of thiyl radical from
a â-thiosubstituted vinyl radical intermediate, and dimer-
ization to give the disulfide (Scheme 11).
We were encouraged to find that isopenem iodide 18
underwent Stille cross-coupling cleanly with some rep-
resentative organotin reagents using 3 mol % of tris-
(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) in the
presence of 6 mol % of triphenylphosphine (Table 4). For
example, reaction of 18 with tributylvinyltin in anhy-
drous DMF provided an 80% yield of adduct 74a .
Employing Pd(OAc)2 as the catalyst, the yield of 74a
improved to 87%. Heteroaromatic rings can also be
introduced onto the bicyclic core of 18, as illustrated in
(53) For examples of palladium-catalyzed reactions on â-lactam ring
systems, see: (a) Barrett, D.; Terasawa, T.; Okuda, S.; Kawabata, K.;
Yasuda, N.; Kamimura, T.; Sakane, K.; Takaya, T. J . Antibiot. 1997,
50, 100. (b) Armitage, M. A.; Lathbury, D. C.; Sweeney, J . B.
Tetrahedron Lett. 1995, 36, 775. (c) Burwood, M.; Davies, B.; Diaz, I.;
Grigg, R.; Molina, P.; Sridharan, V.; Hughes, M. Tetrahedron Lett.
1995, 36, 9053. (d) Rano, T. A.; Greenlee, M. L.; DiNinno, F. P.
Tetrahedron Lett. 1990, 31, 2853. (e) Cook, G. K.; Hornback, W. J .;
J ordan, C. L.; McDonald, J . H.; Munroe, J . E. J . Org. Chem. 1989, 54,
5828. (f) Farina, V.; Baker, S. R.; Hauck, S. I. J . Org. Chem. 1989, 54,
4962. (g) Farina, V.; Baker, S. R.; Benigni, D. A.; Sapino, C. Tetrahe-
dron Lett. 1988, 29, 5739. (h) Farina, V.; Baker, S. R.; Sapino, C.
Tetrahedron Lett. 1988, 29, 6043. (i) Kant, J .; Walker, D. G. In The
Organic Chemistry of â-Lactams, Georg, G. I., Ed.; VCH Publishers:
New York, 1993; pp 121-196. (j) Researchers at SmithKline Beecham
have patented (world patent number WO 9318044-A) interesting
chemistry of cephalosporin triflates where, in the presence of Hunig’s
base, novel [4 + 2]-cycloadducts or substitution products are obtained.
For reactions involving pyrrole, only the substitution product is
observed. For these reactions, an allenyl intermediate is presumed,
and regiochemistry of addition to this species is dependent on the
oxidation state of sulfur (n ) 0 or 1). Readers may refer to the fol-
lowing articles: (a) Elliott, R. L.; Nicholson, N. H.; Peaker, F. E.; Takle,
A. K.; Tyler, J . W.; White, J . J . Org. Chem. 1994, 59, 1606. (b) Elliott,
R. L.; Takle, A. K.; Tyler, J . W.; White, J . J . Org. Chem. 1993, 58,
6954.
Sch em e 11
The sensitivity of compound 31b toward elimination
in metal-mediated halogen exchange reactions prompted
us to consider the use of palladium-catalyzed processes.
The Stille cross-coupling reaction52 of unsaturated halides
and triflates with organostannanes has become a reliable
synthetic method whose mild nature often enables even
difficult transformations to be carried out successfully.
However, only a limited number of reports of Pd(0)-
promoted reactions involving â-lactam frameworks or
functionality similar to that presented in the structures
of our substrates have appeared in the literature.53 The
most pertinent examples are the palladium-catalyzed
couplings of cephem triflates with organotin compounds
used in the preparation of 3-alkenyl, 3-alkynyl, and
3-arylcephem derivatives (eq 10) and the related reac-
tions of carbapenem triflates (eq 11).54
(51) The rate of elimination of a thiyl radical from a â-thioalkyl
radical is on the order of 108 L mol-1 s-1 at room temperature (Wagner,
P.; Sedon, J . H.; Lindstrom, M. J . J . Am. Chem. Soc. 1978, 100, 2579).
For a â-thiovinyl radical, the expulsion of thiyl radical should occur
even more rapidly. See: (a) Benati, L.; Capella, L.; Montevecchi, P.
C.; Spagnola, P. J . Org. Chem. 1994, 59, 2818. (b) Griesbaum, K.
Angew. Chem., Int. Ed. Engl. 1970, 9, 273.
(52) (a) McKean, D. R.; Parrinello, G.; Renaldo, A. F.; Stille, J . K.
J . Org. Chem. 1987, 52, 422. (b) Stille, J . K.; Groh, B. L. J . Am. Chem.
Soc. 1987, 109, 813. (d) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986,
25, 508. (e) Scott, W. J .; Stille, J . K. J . Am. Chem. Soc. 1986, 108,
3033.
(54) (a) Farina, V.; Baker, S. R.; Benigni, D. A.; Hauck, S. I.; Sapino,
C. J . Org. Chem. 1990, 55, 5833. (b) Yasuda, N.; Huffman, M. A.; Ho,
G.-J .; Xavier, L. C.; Yang, C.; Emerson, K. M.; Tsay, F.-R.; Li, Y.; Kress,
M. H.; Rieger, D. L.; Karady, S.; Sohar, P.; Abramson, N. L.; DeCamp,
A. E.; Mathre, D. J .; Douglas, A. W.; Dolling, U.-H.; Grabowski, E. J .
J .; Reider, P. J . J . Org. Chem. 1998, 63, 5438. (c) Narukawa, Y.; Nishi,
K.; Onoue, H. Tetrahedron 1997, 53, 539. (d) Meurer, L. C.; Guthikon-
da, R. N.; Huber, J . L.; DiNinno, F. BioMed. Chem. Lett. 1995, 5, 767.
(e) Yasuda, N.; Xavier, L.; Reiger, D. L.; Li, Y.; DeCamp, A. E.; Dolling,
U.-H. Tetrahedron 1993, 34, 3211. (f) Rano, T. A.; Greenlee, M. L.;
DiNinno, F. Tetrahedron Lett. 1990, 31, 2853.

Nonconventionally Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 63, No. 24, 1998 8911
Ta ble 4. P a lla d iu m -P r om oted Cr oss-Cou p lin g
Rea ction s of â-La cta m 18 w ith Or ga n osta n n a n es
ous media as a means to prepare carboxylic acid deriva-
tives directly from the vinyl iodides. Palladium-assisted
carboxylations of this type are rare and rather limited
in scope.57 Moreover, we are unaware of any reports of
palladium-catalyzed carboxylation reactions involving
â-lactam ring systems. Despite our concern that the
hydrolytic conditions of the reaction may cleave the
â-lactam moiety, substrates 18, 31a , and 56a were found
to undergo the desired transformation to carboxylic acids
79-81, respectively, in hydrous dimethylformamide solu-
tion (eq 14). Optimal conditions for this reaction require
that only a minimal amount of water (<1%) be added to
the solution and that the reactions be run at tempera-
tures no higher than ambient. Despite the long reaction
times required for completion (3-5 days), the â-lactam
ring is not opened under these conditions, and the desired
carboxylic acids can be obtained in 65-75% isolated yield
after purification by flash chromatography. The struc-
tures of the acids were confirmed by 1H NMR in two
different deuterated solvents (CDCl3 and DMSO-d6), as
well as through conversion to their methyl esters using
ethereal diazomethane. Interestingly, in the carboxyla-
tion of â-lactam 31a , a small amount (5-10%) of thioester
82 was also obtained through a yet unidentified pathway.
the formation of furan adduct 74b and indole55 adduct
74c. These examples demonstrate the compatibility of
the reaction conditions with respect to the presence of
the vinyl sulfide and â-lactam ring in 18 during the
alkylation reaction and pointed to the likelihood that
related palladium-promoted processes might also prove
effective.
Upon additional investigation, we were pleased to find
that palladium catalysis can be extended to CO insertion
reactions of 18 for synthesizing carboxylic ester and acid
derivatives. As shown in eq 12, iodo compound 18
provided good yields of the desired methyl and allyl esters
75 and 76 using 3-5 mol % of Pd2(dba)3 in a mixed
alcohol-dimethylformamide solvent under an atmo-
sphere of carbon monoxide.56 Although these esterifica-
Disappointingly, application of the palladium-catalyzed
CO insertion reactions using isopenem 39b failed to
deliver carboxylic acid derivative 83 (eq 15). Instead, a
high yield of ring-opened disulfides 84 was obtained,
which we later determined was the result of cleavage of
the nitrogen-sulfur bond by PPh3 in the reaction medium
(eq 16). In an attempt to circumvent this problem, we
examined the palladium-promoted carboxylation of sul-
fonamide derivative 58a . Unfortunately, the reaction did
not yield the carboxylic acid 85 (eq 17) but rather the
ring-cleaved sulfinic acid 86 in 95% yield (eq 18).
tions proceed well at room temperature, it was possible
to run them at a slightly elevated temperature (55 °C)
to increase the rate of conversion. Similarly, R-ethylthio
â-lactam derivative 31a and bis-sulfone 56a underwent
the CO insertion process to provide their corresponding
methyl esters 77 and 78, respectively (eq 13).
The efficiency of these esterifications encouraged us
to consider carrying out CO insertion reactions in aque-
(57) (a) Tsuji, J .; Takahashi, M.; Takahashi, T. Tetrahedron Lett.
1980, 21, 849. (b) Fenton, D. M. J . Org. Chem. 1973, 38, 3192. (c)
Larock, R. C. J . Org. Chem. 1975, 40, 3237. (d) Cassar, L.; Foa, M.;
Gardano, A. J . Organometallic Chem. 1976, 121, C55. (e) Fujiwara,
Y.; Kawauchi, T.; Taniguchi, H. J . Chem. Soc., Chem. Commun. 1980,
220. (f) Alper, H.; Hashem, K.; Heveling, J . Organometallics 1982, 1,
775.
(55) For a related example of a Stille reaction involving an indole
nucleus, see: Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1994, 35, 2405.
(56) (a) Grigg, R.; Sridharan, V.; Sukirthalingam, S.; Worakun, T.
Tetrahedron Lett. 1989, 30, 1139. (b) Schoenberg, A.; Bartoletti, I.;
Heck, R. F. J . Org. Chem. 1974, 39, 3318.

8912 J . Org. Chem., Vol. 63, No. 24, 1998
Ren et al.
marcesceus. All other compounds were inactive against
the strains tested. It would appear from these prelimi-
nary findings that the relocation of the lactam moiety
within the classical bicyclic â-lactam framework has a
detrimental effect on biological activity, reflecting the
precision in which bioactive molecules must bind and
interact with active site functionality. However, efforts
are underway to prepare and study more highly func-
tionalized â-lactam derivatives to address this issue more
definitively.58
Exp er im en ta l Section
All air- or moisture-sensitive reactions were performed
under an argon atmosphere using glassware and syringes that
were predried overnight in an oven at 120 °C and assembled
while still hot. Reactions generating unpleasant or noxious
odors were carried out in an efficient fume hood. The imines
used in this study were prepared by heating equimolar
amounts of the appropriate aldehyde and amine in refluxing
benzene solution in the presence of a small amount of p-
toluenesulfonic acid under Dean-Stark conditions, followed
by filtering the cooled solution through a 1-in. plug of silica
gel to remove residual amine. The purity of the crude imine
was checked by 1H NMR prior to use. The acid chlorides were
synthesized according to standard protocols by heating the
corresponding carboxylic acid in thionyl chloride (removing
residual volatiles by distillation) and used without further
purification. THF and Et2O were distilled immediately prior
to use from Na/benzophenone under argon, and CH2Cl2 was
freshly distilled from CaH2 under N2. Reactions were followed
by TLC using EM Reagents plates with fluorescence indicator
(SiO2-60, F-254) or 1% aqueous KMnO4 stain. Flash chroma-
tography was performed using J .T. Baker flash chromatogra-
phy silica gel (40 µm). 1H NMR spectra were recorded at 300,
360, 400, or 500 MHz, and 13C NMR spectra were obtained at
75, 100, or 125 MHz, as indicated. IR spectra were obtained
as a thin film smeared onto NaCl plates. Melting points are
uncorrected. Mass spectra were run using electron impact or
chemical ionization methods as noted. Elemental analyses
were performed by Atlantic Microlab (Atlanta, GA).
The p-methoxyphenyl N-protecting group of com-
pounds 80 and 82 was oxidatively cleaved using ceric
ammonium nitrate in aqueous acetonitrile to afford the
free â-amino acid and thioester derivatives 87 and 88,
each in about 75% yield (eq 19).
P r oced u r e for th e P r ep a r a tion of Mon ocyclic â-La c-
ta m s 17 a n d 20. To a stirred solution of Et3N (1.25 mL, 8.97
mmol) and imine 16 (2.11 g, 8.92 mmol) in THF (60 mL) at
-78 °C was added via cannula a solution of S-benzylthioacetyl
chloride (15, 1.77 g, 9.0 mmol) in THF (20 mL). The reaction
mixture was stirred at -78 °C for 30 min, warmed to RT, and
then poured into 5% aqueous HCl and extracted with CH2Cl2
(3 × 50 mL). The combined organic layers were dried over
MgSO4, filtered, and evaporated to give a dark brown oil.
Flash chromatography (2:1 CH2Cl2:hexanes and then CH2Cl2)
of the resulting material afforded 3.14 g (89%) of â-lactam 17
as a 10:1 mixture of trans:cis isomers.
One final transformation we would like to report is the
ozonolysis of vinyl substrate 74a to aldehyde 89 (eq 20).
The cleavage reaction proceeds quickly upon bubbling a
dilute stream of O3 through a dichloromethane solution
of 74a at room temperature, to provide aldehyde 89. The
aldehyde can potentially open new avenues for introduc-
ing other types of functionality onto the core of these
â-lactam ring systems.
To a stirred solution of the above crude product mixture
(3.14 g, 7.87 mmol) in THF (80 mL) at -78 °C was added
n-BuLi (4.80 mL, 1.8 M solution in hexanes, 8.64 mmol). The
reaction mixture was stirred for 15 min, poured into 5%
aqueous HOAc, and extracted with CH2Cl2 (3 × 20 mL), and
the combined organic layers were dried over MgSO4, filtered,
and then evaporated. Flash chromatography of this material
gave 3.12 g (88% overall, 2:1 mixture of cis:trans isomers) of
17 as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.45-
7.25 (m, 12H), 6.94 (d, J ) 8.4 Hz, 2H, cis isomer), 6.91 (d, J
) 8.4 Hz, 2H, trans isomer), 5.00 (d, J ) 4.9 Hz, 1H, cis
isomer), 4.39 (d, J ) 4.9 Hz, 1H, cis isomer), 4.30 (AB m, 2H,
trans isomer), 4.07 (AB m, 2H, cis isomer), 3.95 (s, 2H, trans
isomer), 3.79 (2 overlapping s, total 3H, cis and trans isomers);
13C NMR (75 MHz, CDCl3) (trans isomer) δ 162.1, 157.6, 138.0,
132.4, 131.2, 129.9, 129.8, 129.5, 128.1, 128.0, 122.1, 119.1,
Each of the bicyclic â-lactams synthesized in our study
was screened against a battery of common Gram-positive
and Gram-negative microorganisms on tryptic soy agar
using the disk diffusion method. Approximately 50 µg
of each compound was deposited onto cellulose disks, and
circular zones where bacterial growth was inhibited were
measured. These preliminary tests indicate that com-
pounds 58b, 80, 87, and 89 have weak antibacterial
activity against either Staphylococcus aureus or Vibrio
cholerae but are ineffective against E. cloacae, E. coli, K.
pneumoniae, P. aeruginosa, S. typhimurium, and S.
(58) For a discussion on the bioactivation of â-lactam antibiotics
having bicyclic frameworks, see: Rando, R. Acc. Chem. Res. 1975, 8,
281.

Nonconventionally Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 63, No. 24, 1998 8913
115.0, 88.4, 83.9, 58.0, 55.9, 51.0, 35.9; IR (thin film) 1750 cm-1
(â-lactam CdO); HRMS (CI, isobutane) calcd for C25H21NO2S
HRMS (CI, isobutane) calcd for C18H25NOS2 (M + 1) 336.1450,
obsd 336.1452. Anal. Calcd for C18H25NOS2: C, 64.43; H, 7.51.
Found: C, 64.52; H, 7.29.
(M + 1) 400.1366, obsd 400.1371. Anal. Calcd for C25H21
NO2S: C, 75.16; H, 5.30. Found: C, 75.01; H, 5.35.
A similar procedure was used to prepare 20.
-
36b: 4.1 g (92%); colorless crystals (mp 172-173 °C); 1H
NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 7.75 (m, 2H), 7.58 (d,
J ) 8.8 Hz, 2H), 7.30-7.15 (m, 5H), 6.92 (d, J ) 8.8 Hz, 2H),
5.71 (d, J ) 4.8 Hz, 1H), 5.18 (d, J ) 4.8 Hz, 1H), 3.80 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 167.5, 160.4, 157.5, 135.2, 132.5,
132.4, 131.2, 129.7, 128.9, 124.5, 122.0, 119.4, 115.2, 90.5, 81.4,
58.5, 56.2, 50.3. Anal. Calcd for C26H18N2O4: C, 73.92; H,
4.30. Found: C, 73.72; H, 4.37.
20: 5.25 g (77%, 1:3 cis:trans mixture); colorless oil; 1H NMR
(400 MHz, CDCl3) δ 7.36-7.21 (m, 7H), 6.82 (d, J ) 8.8 Hz, 2
× 2H, cis and trans isomers), 5.30 (d, J ) 9.6 Hz, 1H, cis
isomer), 5.06 (d, J ) 9.8 Hz, 1H, trans isomer), 4.75 (dd, J )
4.9, 9.6 Hz, 1H, cis isomer), 4.23 (dd, J ) 2.0, 9.8 Hz, 1H, trans
isomer), 3.85 (m, 2 × 2H, cis and trans isomers), 3.80 (s, 3H,
cis isomer), 3.75 (s, 3H, trans isomer), 1.80 (s, 3H, cis isomer),
1.78 (s, 3H, cis isomer), 1.67 (s, 3H, trans isomer), 1.65 (s, 3H,
trans isomer); 13C NMR (75 MHz, CDCl3) (trans isomer) δ
163.5, 157.0, 140.1, 138.4, 132.0, 130.0, 129.2, 127.9, 122.0,
119.0, 114.8, 58.2, 56.4, 55.9, 35.6, 26.1, 18.6; IR (thin film)
1750 cm-1 (â-lactam CdO); HRMS (CI, isobutane) calcd for
48a : 4.7 g (89%); colorless crystals (mp 96-99 °C); 1H NMR
(400 MHz, CDCl3) δ 7.32 (d, J ) 8.8 Hz, 2H), 6.78 (d, J ) 8.8
Hz, 2H), 5.97 (dq, J ) 7.0, 15.6 Hz, 1H), 5.52 (dd, J ) 8.8,
15.6 Hz, 1H), 4.54 (d, J ) 4.8 Hz, 1H), 4.50 (dd, J ) 4.8, 8.8
Hz, 1H), 3.79 (s, 3H), 3.52 (s, 3H), 1.78 (d, J ) 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 164.4, 156.9, 134.2, 131.8, 125.7,
119.2, 114.7, 84.8, 60.8, 59.0, 55.7, 18.3; IR (thin film) 1742
cm-1 (â-lactam CdO). Anal. Calcd for C14H17NO3: C, 68.00;
H, 6.93. Found: C, 68.23; H, 6.99.
C
21H23NO2S (M + 1) 354.1522, obsd 354.1526. Anal. Calcd
for C21H23NO2S: C, 71.36; H, 6.56. Found: C, 71.29; H, 6.65.
P r oced u r e for t h e P r ep a r a t ion of N-Ar yl-P r ot ect ed
â-La cta m s. To a stirred solution of Et3N (1.25 mL, 9.0 mmol)
and imine 16 (1.88 g, 8.0 mmol) in CH2Cl2 (75 mL) at room
temperature is added via cannula a solution of methoxyacetyl
chloride (35a , 0.91 g, 10.0 mmol) in CH2Cl2 (20 mL). The
reaction mixture is stirred at room temperature for 30 min,
poured into 5% aqueous HCl (75 mL), and extracted with CH2-
Cl2 (3 × 50 mL). The combined organic layers are dried over
MgSO4, filtered, and evaporated to give a brown oil that slowly
crystallized upon standing. Flash chromatography (2:1 CH2-
Cl2:hexanes and then CH2Cl2) of the crude material afforded
2.20 g (89%) of â-lactam 36a : white solid; 116-117 °C; 1H
NMR (400 MHz, CDCl3) δ 7.54-7.35 (m, 7H), 6.90 (d, J ) 7.8
Hz, 2H), 4.96 (d, J ) 4.8 Hz, 1H), 4.81 (d, J ) 4.8 Hz, 1H),
3.78 (s, 3H), 3.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.1,
157.4, 132.6, 129.3, 129.2, 129.1, 128.8, 119.1, 115.0, 84.8, 81.7,
59.1, 56.1, 56.0, 50.3; IR (thin film) 1752 cm-1 (â-lactam CdO).
Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56.
Found: C, 74.10; H, 5.60; N, 4.57.
48b: 3.6 g (88%); colorless crystals (mp 161-162 °C); 1H
NMR (400 MHz, CDCl3) δ 7.89 (d, J ) 8.8 Hz, 2H), 7.76 (d, J
) 8.8 Hz, 2H), 7.40 (d, J ) 8.8 Hz, 2H), 6.82 (d, J ) 8.8 Hz,
2H), 5.95 (m, 1H), 5.55 (m, 2H), 4.82 (dd, J ) 4.9, 7.8 Hz, 1H),
3.80 (s, 3H), 1.62 (d, J ) 7.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.9, 161.3, 157.1, 135.7, 135.0, 132.3, 131.9, 125.1,
124.3, 119.3, 114.9, 61.0, 57.9, 55.8, 18.1. Anal. Calcd for
C
21H18N2O4: C, 69.60; H, 5.01. Found: C, 69.78; H, 5.12.
P r oced u r e for th e Ozon olysis of Alk en yl â-La cta m s.
To a solution of olefinic â-lactam 48a (3.72 g, 15.0 mmol) in
CH2Cl2 (150 mL) at RT is bubbled a slow stream of ozone in
air. The progress of the reaction is monitored by 1H NMR until
all of the starting olefin is consumed. The mixture is then
poured into water and extracted with CH2Cl2 (4 × 50 mL),
and the combined organic layers are dried over MgSO4,
filtered, and evaporated. Flash chromatography of the crude
mixture affords 3.35 g (95%) of aldehyde 49a as a colorless
oil, which was used immediately in the next step: 1H NMR
(400 MHz, CDCl3) δ 9.78 (d, J ) 4.0 Hz, 1H), 7.25 (d, J ) 8.8
Hz, 2H), 6.85 (d, J ) 8.8 Hz, 2H), 4.86 (d, J ) 6.0 Hz, 1H),
4.52 (dd, J ) 4.0, 6.0 Hz, 1H), 3.86 (s, 3H), 3.58 (s, 3H).
A similar procedure was used to prepare aldehydes 49b and
89.
A similar procedure was used to make the following
compounds.
30a : 1.39 g (88%); colorless oil; 1H NMR (400 MHz, CDCl3)
δ 7.54-7.27 (m, 7H), 6.89 (d, J ) 8.8 Hz, 2H), 4.95 (s, 1H),
3.74 (s, 3H), 3.14-2.89 (m, 4H), 1.35-1.31 (m, 6H); 13C NMR
(75 MHz, CDCl3) δ 162.5, 157.5, 132.6, 131.0, 129.9, 129.6,
122.1, 119.6, 115.1, 91.5, 81.9, 70.0, 58.0, 55.5, 24.6, 24.5, 14.4,
14.2; IR (thin film) 1752 cm-1 (â-lactam CdO); HRMS (CI,
isobutane) calcd for C22H23NO2S2 (M + 1) 398.1243, obsd
398.1255. Anal. Calcd for C22H23NO2S2: C, 66.47; H, 5.83.
Found: C, 66.18; H, 5.60.
49b: 2.35 g (90%); colorless oil; 1H NMR (400 MHz, CDCl3)
δ 9.50 (d, J ) 3.2 Hz, 1H), 7.86-7.76 (m, 4H), 7.38 (d, J ) 8.8
Hz, 2H), 6.85 (d, J ) 8.8 Hz, 2H), 5.80 (d, J ) 6.0 Hz, 1H),
4.78 (dd, J ) 3.2, 6.0 Hz, 1H), 3.80 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 198.3, 167.5, 161.2, 157.8, 135.5, 134.9, 132.0, 131.1,
124.6, 124.2, 118.6, 115.4, 63.1, 55.9.
1
30b: 2.1 g (95%); colorless oil; H NMR (400 MHz, CDCl3)
89: 0.15 g (96%); colorless oil; 1H NMR (400 MHz, CDCl3) δ
9.47 (s, 1H), 7.75-6.85 (m, 9H), 5.88 (d, J ) 6.0 Hz, 1H), 5.00
(d, J ) 6.0 Hz, 1H), 3.78 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
185.3, 133.0, 131.8, 131.7, 130.3, 130.2, 129.2, 129.1, 129.0,
128.4, 119.5, 119.4, 114.3, 114.2, 55.5. HRMS (CI, isobutane)
calcd for C19H13NO3S (M + 1) 338.0847, obsd 338.0852. Anal.
Calcd for C19H13NO3S: C, 67.64; H, 4.48.
δ 7.44-7.28 (m, 10H), 4.78 (d, J ) 14.8 Hz, 1H), 4.42 (s, 1H),
4.23 (d, J ) 14.8 Hz, 1H), 3.04-2.80 (m, 2H), 1.33-1.25 (m,
6H); 13C NMR (75 MHz, CDCl3) δ 166.0, 135.5, 132.5, 129.9,
129.7, 129.0, 128.5, 127.5, 122.2, 95.0, 82.0, 70.9, 58.0, 45.0,
25.1, 25.0, 14.5, 14.2;; IR (thin film) 1765 cm-1 (â-lactam CdO);
HRMS (CI, isobutane) calcd for C22H23NOS2 (M + 1) 382.1294,
obsd 382.1301. Anal. Calcd for C22H23NOS2: C, 69.25; H, 6.08.
Found: C, 69.48; H, 6.10.
P r oced u r e for th e Gr ign a r d Rea ction of Ald eh yd es 49.
To a solution of phenylacetylene (1.56 g, 15.0 mmol) in THF
(75 mL) at -78 °C under nitrogen is added n-BuLi (11.0 mL,
1.43 M in hexanes, 15.7 mmol), and the mixture is stirred for
30 min. To the above mixture is added anhydrous MgBr2 (2.90
g, 15.5 mmol), and the mixture is stirred vigorously while
warming to RT until the solid MgBr2 completely dissolves.
To a solution of aldehyde 49a (3.35 g, 14.2 mmol) in THF
(50 mL) at -78 °C under N2 is added slowly through cannula
the above freshly prepared Grignard reagent. The reaction
mixture is stirred for 30 min, warmed to RT, and then poured
into 5% aqueous ammonium chloride solution (30 mL). The
aqueous mixture is extracted with CH2Cl2 (3 × 50 mL), and
the combined organic layers are dried over MgSO4, filtered,
and evaporated. Flash chromatography of the crude mixture
affords 4.02 g (69%, 5:1 mixture) of the hydroxy â-lactam as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.40-7.21 (m, 7H),
6.80 (d, J ) 8.8 Hz, 2H), 5.06 (d, J ) 9.0 Hz, 1H), 4.70 (d, J )
4.9 Hz, 1H), 4.39 (dd, J ) 4.9, 9.0 Hz, 1H), 3.69 (s, 3H), 3.66
30c: 0.183 g (94%); colorless oil; 1H NMR (400 MHz, CDCl3)
δ 7.35-7.22 (m, 5H), 4.65 (d, J ) 15.6 Hz, 2H), 4.15 (s, 1H),
4.09 (d, J ) 15.6 Hz, 2H), 2.90 (m, 1H), 2.84-2.72 (m, 3H),
1.28-1.19 (m, 6H), 0.99 (t, J ) 8.0 Hz, 9H), 0.59 (q, J ) 8.0
Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 165.9, 135.6, 129.8,
129.0, 128.5, 98.9, 94.8, 70.1, 58.0, 42.9, 25.0, 24.9, 14.8, 14.1,
7.8, 4.2; IR (thin film) 1770 cm-1 (â-lactam CdO). HRMS (CI,
isobutane) calcd for C22H33NOS2Si (M + 1) 420.1843, obsd
420.1833. Anal. Calcd for C22H33NOS2Si: C, 62.96; H, 7.93.
Found: C, 63.11; H, 7.62.
33: 0.261 g (58%) obtained as a colorless oil; 1H NMR (400
MHz, CDCl3) δ 7.35-7.19 (m, 5H), 5.24 (d, J ) 9.6 Hz, 1H),
4.65 (d, J ) 14.8 Hz, 1H), 4.15 (d, J ) 9.6 Hz, 1H), 3.93 (d, J
) 14.8 Hz, 1H), 2.90-2.64 (m, 4H), 1.76 (s, 3H), 1.44 (s, 3H),
1.28-1.19 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 166.6, 142.2,
136.0, 129.5, 129.0, 128.1, 119.1, 70.4, 63.5, 44.3, 26.2, 24.3,
24.1, 18.5, 14.5, 14.4; IR (thin film) 1760 cm-1 (â-lactam CdO).

8914 J . Org. Chem., Vol. 63, No. 24, 1998
Ren et al.
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.9, 157.4, 132.2, 130.5,
129.3, 129.0, 122.6, 120.0, 114.9, 87.5, 85.5, 84.3, 61.0, 60.8,
55.8; IR (thin film) 3500-3200 (OH), 1750 cm-1 (â-lactam Cd
O).
Azetid in yl Alcoh ol fr om 49b: 2.29 (80%, 2:1 mixture);
colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.80-6.82 (m, total
13H), 5.63 (m, total 1H), 5.10 (m, total 1H), 4.68 (m, total 1H),
3.75 (s, total 3H); IR (thin film) 3600-3200, 1780 (phthalimidyl
CdO), 1750 cm-1 (â-lactam CdO).
12.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 166.7, 137.8, 132.4,
129.9, 129.7, 129.4, 129.1, 128.3, 122.5, 87.3, 85.5, 60.3, 48.1,
36.2; IR (thin film) 1770 cm-1 (â-lactam CdO). Anal. Calcd
for C18H15NOS: C, 73.69; H, 5.15. Found: C, 73.84; H, 4.98.
51a : 0.34 g (5:1 mixture, 91%). Data for major isomer:
colorless crystals (decomposed at 165-169 °C); 1H NMR (400
MHz, CDCl3) δ 7.44-7.26 (m, 5H), 6.55 (s, 1H), 5.70 (d, J )
6.8 Hz, 1H), 4.57 (d, J ) 5.0 Hz, 1H), 4.01 (dd, J ) 5.0, 6.8 Hz,
1H), 3.50 (s, 3H), 2.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
170.0, 168.6, 132.6, 129.6, 128.9, 122.2, 88.0, 84.8, 83.7, 63.6,
59.8, 56.3, 21.0; IR (thin film) 3350-3200 (N-H), 1780
(â-lactam CdO), 1750 cm-1 (acetate CdO). Anal. Calcd for
P r oced u r e for th e Acyla tion of Alcoh ols. To a solution
of the above hydroxy â-lactam (4.02 g, 9.6 mmol, prepared from
49a ) in DMSO (10 mL) and pyridine (4 mL) is added a catalytic
amount of 4-(N,N-dimethylamino)pyridine. To this mixture
is added dropwise anhydrous acetic anhydride (5.0 mL, 50
mmol). The reaction mixture is stirred overnight and then
poured into a 5% HCl solution (75 mL). The aqueous layer is
extracted with CH2Cl2 (3 × 50 mL), and the combined organic
layers are dried over MgSO4, filtered, and evaporated. Flash
chromatography of the crude mixture affords 3.30 g (5:1
mixture, 80% from alcohol) of acetates 50a as a colorless oil,
with partial separation of the isomers. Data for major
isomer: 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J ) 8.8 Hz, 2H),
7.25-7.18 (m, 5H), 6.82 (d, J ) 8.8 Hz, 2H), 6.02 (d, J ) 3.0
Hz, 1H), 4.68 (d, J ) 3.0 Hz, 1H), 4.50 (dd, J ) 3.0, 4.9 Hz,
1H), 3.75 (s, 3H), 3.62 (s, 3H), 2.15 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.1, 165.2, 157.3, 132.4, 131.2, 129.4, 129.0, 128.7,
120.1, 114.7, 89.3, 83.2, 83.0, 63.6, 60.4, 60.1, 55.7, 21.1; IR
(thin film) 1750 (â-lactam CdO), 1735 cm-1 (acetate CdO).
Data for minor isomer: 1H NMR (400 MHz, CDCl3) δ 7.49 (d,
J ) 8.8 Hz, 2H), 7.25-7.18 (m, 5H), 6.82 (d, J ) 8.8 Hz, 2H),
6.02 (d, J ) 3.0 Hz, 1H), 4.68 (d, J ) 3.0 Hz, 1H), 4.66 (dd, J
) 3.0, 4.9 Hz, 1H), 3.79 (s, 3H), 3.65 (s, 3H), 1.86 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 170.1, 165.2, 157.5, 132.5, 129.6,
128.9, 122.3, 120.7, 114.6, 111.3, 87.8, 84.3, 83.6, 63.6, 60.7,
60.1, 55.8, 20.8; IR (thin film) 1750 (â-lactam CdO), 1735 cm-1
(acetate CdO). Anal. Calcd for C22H21NO5: C, 69.65; H, 5.58.
Found: C, 69.41; H, 5.31.
C
15H15NO4: C, 65.92; H, 5.53. Found: C, 66.31; H, 5.29.
51b: 0.27 g (2:1 mixture, 87%); colorless oil. Data for major
isomer: colorless crystals (decomposed at 170-172 °C); 1H
NMR (400 MHz, CDCl3) δ 7.82-6.98 (m, 9H), 6.42 (s, 1H), 5.90
(d, J ) 9.0 Hz, 1H), 5.42 (d, J ) 4.9 Hz, 1H), 4.30 (m, 1H),
2.02 (s, 3H). Anal. Calcd for C22H16N2O5: C, 68.04; H, 4.15.
Found: C, 67.93; H, 4.05. Data for minor isomer: δ 7.82-
6.98 (m, 9H), 6.60 (s, 1H), 5.75 (d, J ) 9.0 Hz, 1H), 5.62 (d, J
) 4.9 Hz, 1H), 4.30 (m, 1H), 2.12 (s, 3H).
87: 0.055 g (74%); colorless oil; 1H NMR (360 MHz, DMSO-
d6) δ 9.03 (s, 1H), 7.04 (m, 5H), 4.66 (s, 1H), 2.51 (app q, J )
7.2 Hz, 2H), 0.90 (t, J ) 7.4 Hz, 3H); 13C NMR (90 MHz,
DMSO-d6) δ 164.1, 163.2, 159.0, 132.4, 129.9, 129.4, 128.2,
121.3, 71.3, 31.6, 24.2, 14.8; IR (film) 1750 (â-lactam CdO),
1725 cm-1 (carboxylic acid CdO). Anal. Calcd for C14H13
-
NO3S2: C, 54.70; H, 4.26. Found: C, 54.68; H, 4.22.
88: 0.015 g (75%); white crystals (mp 116-118 °C); 1H NMR
(500 MHz, CDCl3) δ 7.42-7.40 (m, 5H), 6.50 (br s, 1H), 5.20
(s, 1H), 2.95 (AB m, 2H), 2.83 (q, J ) 7.5 Hz, 2H), 1.38 (t, J )
7.5 Hz, 3H), 1.18 (t, J ) 7.5 Hz, 3H). HRMS (CI, isobutane)
calcd for C16H17NO2S3 (M + 1) 352.0496, obsd 352.0492. Anal.
Calcd for C16H17NO2S3: C, 54.67; H, 4.87. Found: C, 54.82;
H, 4.92.
P r oced u r e for th e N-Meth ylth iola tion of â-La cta m s.
To a solution of 37a (1.28 g, 6.4 mmol) in THF at -78 °C is
added n-butyllithium (5.0 mL, 1.38 M in hexanes, 6.9 mmol).
After 30 min, methyl methanethiolsulfonate (0.85 g, 6.6 mmol)
is added and the reaction mixture is stirred for 12 h with
warming to RT. The mixture is poured into 5% aqueous NH4-
Cl (50 mL) and extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers are dried over MgSO4, filtered, and
evaporated. Flash chromatography of the crude mixture
affords 1.26 g (80%) of N-methylthio compound 38a : colorless
solid; mp 74-76 °C; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J )
8.8 Hz, 2H), 7.30 (m, 3H), 4.72 (d, J ) 4.8 Hz, 1H), 4.63 (d, J
) 4.8 Hz, 1H), 3.56 (s, 3H), 2.58 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 169.8, 132.4, 129.6, 129.0, 122.5, 89.3, 86.6, 82.5, 59.0,
55.1, 22.7; IR (thin film) 1772 cm-1 (â-lactam CdO). HRMS
(CI, isobutane) calcd for C13H13NO2S (M + 1) 248.0742, obsd
248.0734. Anal. Calcd for C13H13NO2S: C, 63.13; H, 5.30.
Found: C, 63.08; H, 5.33.
A similar procedure was used to prepare acetate 50b.
50b: 2.13 g (2:1 mixture, 85% from alcohol); Data for major
isomer: colorless crystals (mp 195-196 °C); 1H NMR (400
MHz, CDCl3) δ 7.76-6.78 (m, 13H), 6.08 (d, J ) 5.9 Hz, 1H),
5.56 (d, J ) 6.8 Hz, 1H), 4.75 (dd, J ) 5.9, 6.8 Hz, 1H), 3.65
(s, 3H), 1.81 (s, 3H). Anal. Calcd for C29H22N2O6: C, 70.44;
H, 4.48. Found: C, 70.16; H, 4.32. Data for minor isomer: δ
7.76-6.78 (m, 13H), 5.98 (d, J ) 9.0 Hz, 1H), 5.68 (d, J ) 5.9
Hz, 1H), 4.84 (dd, J ) 5.9, 9.0 Hz, 1H), 3.70 (s, 3H), 2.08 (s,
3H).
P r oced u r e for th e Dea r yla tion of N-Ar yl â-La cta m s.
To a solution of N-p-methoxyphenyl â-lactam 36a (2.2 g, 7.2
mmol) in CH3CN (100 mL) at 0 °C is added 100 mL of an
aqueous solution of ammonium cerium(IV) nitrate (11.8 g, 21.6
mmol) over 5 min. The reaction mixture is stirred for 25 min
and then poured into aqueous 5% NaHSO3 (100 mL), and the
aqueous mixture is extracted with Et2O (3 × 50 mL). The
combined organic layers are treated with 5% aqueous NaHCO3
(100 mL), and the aqueous layer is back-washed with one
portion of diethyl ether (50 mL). The combined organic layers
are dried over MgSO4, filtered, and evaporated. Flash chro-
matography of the crude mixture affords 1.28 g (89%) of 37a :
white solid (mp 121-122 °C); 1H NMR (400 MHz, CDCl3) δ
7.42-7.35 (m, 5H), 6.80 (broad s, 1H), 4.72 (d, J ) 4.8 Hz,
1H), 4.60 (d, J ) 4.8 Hz, 1H), 3.60 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.5, 132.4, 129.4, 128.9, 122.7, 87.9, 87.1, 83.7, 58.8,
46.6. HRMS (CI, isobutane) calcd for C12H11NO2 (M + 1)
202.0865, obsd 202.0884. Anal. Calcd for C12H11NO2: C,
71.63; H, 5.51; N, 6.96. Found: C, 71.55; H, 5.53; N, 6.91.
38b: 0.93 g (90%); colorless solid (mp 203-205 °C); 1H NMR
(400 MHz, CDCl3) δ 7.85 (dd, J ) 2.9, 4.9 Hz, 2H), 7.73 (dd, J
) 2.9, 4.9 Hz, 2H), 7.26-7.12 (m, 5H), 5.63 (d, J ) 4.8 Hz,
1H), 4.91 (d, J ) 4.8 Hz, 1H), 2.78 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.5, 167.4, 135.2, 135.1, 132.2, 129.7, 128.9, 124.3,
121.9, 90.3, 82.0, 60.2, 54.5, 49.2, 22.5. HRMS (CI, isobutane)
calcd for C20H14N2O3S (M + 1) 363.0800, obsd 363.0780. Anal.
Calcd for C20H14N2O3S: C, 66.28; H, 3.89. Found: C, 66.43;
H, 3.92.
41: 0.35 g (87%); colorless oil; 1H NMR (360 MHz, CDCl3) δ
5.95 (dq, J ) 7.0, 15.6 Hz, 1H), 5.54 (dd, J ) 8.8, 15.6 Hz,
1H), 4.61 (d, J ) 4.8 Hz, 1H), 4.18 (dd, J ) 4.8, 8.8 Hz, 1H),
3.47 (s, 3H), 2.43 (s, 3H), 1.82 (d, J ) 7.0 Hz, 3H);13C NMR
(90 MHz, CDCl3) δ 170.4, 134.8, 124.5, 85.8, 65.3, 58.7, 22.7,
18.2. Anal. Calcd for C8H13NO2S: C, 51.31; H, 7.00. Found:
C, 51.67; H, 6.75.
1
37b: 0.46 g (92%); colorless crystals (mp 195-197 °C); H
NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 7.75 (m, 2H), 7.25-
7.18 (m, 5H), 6.58 (broad s, 1H), 5.61 (d, J ) 4.2 Hz, 1H), 4.90
(d, J ) 4.2 Hz, 1H); IR (thin film) 3350-3200 (N-H), 1780
(phthalimidyl CdO), 1770 cm-1 (â-lactam CdO). Anal. Calcd
for C19H12N2O3: C, 72.15; H, 3.82. Found: C, 72.01; H, 3.86.
45: 0.73 g (88%); white crystals (mp 135-137 °C); 1H NMR
(400 MHz, CDCl3) δ 7.40-7.24 (m, H), 6.07 (br s, 1H), 4.22 (br
d, J ) 2.4 Hz, 1H), 4.16 (d, J ) 2.4 Hz, 1H), 3.91 (app q, J )
46: 0.15 g (85%); colorless oil; 1H NMR (400 MHz, CDCl3) δ
7.42-7.25 (m, 10H), 4.20 (d, J ) 2.4 Hz, 1H), 4.14 (d, J ) 2.4
Hz, 1H), 3.90 (app q, J ) 13.2 Hz, 2H), 2.54 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 169.2, 137.6, 132.4, 129.8, 129.5, 129.2,
128.4, 122.3, 88.7, 84.7, 59.2, 56.2, 36.3, 23.3. Anal. Calcd
for C19H17NOS2: C, 67.22; H, 5.05. Found: C, 67.20; H, 5.13.

Nonconventionally Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 63, No. 24, 1998 8915
52a (one isomer, 81%): colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.44-7.26 (m, 5H), 5.80 (d, J ) 6.8 Hz, 1H), 4.60 (d,
J ) 5.0 Hz, 1H), 4.02 (dd, J ) 5.0, 6.8 Hz, 1H), 3.48 (s, 3H),
2.48 (s, 3H), 2.08 (s, 3H). Anal. Calcd for C16H17NO4S: C,
60.17; H, 5.37. Found: C, 60.28; H, 5.33.
52b (5:1 mixture, 92%): colorless oil. Data for major isomer:
1H NMR (400 MHz, CDCl3) δ 7.80-7.24 (m, 9H), 5.88 (d, J )
8.0 Hz, 1H), 5.47 (d, J ) 6.0 Hz, 1H), 4.30 (dd, J ) 6.0, 8.0 Hz,
1H), 2.57 (s, 3H), 1.80 (s, 3H). Data for minor isomer: δ 7.80-
7.24 (m, 9H), 5.90 (d, J ) 9.8 Hz, 1H), 5.64 (d, J ) 6.0 Hz,
1H), 4.36 (dd, J ) 6.0, 9.8 Hz, 1H), 2.52 (s, 3H), 2.14 (s, 3H);
13C NMR (75 MHz, CDCl3) (5:1 mixture) δ 170.0, 167.8, 167.7,
135.1, 132.3, 132.0, 129.6, 128.6, 124.3, 88.4, 82.0, 64.9, 63.1,
56.6, 22.7, 21.1. Anal. Calcd for C23H18N2O5S: C, 63.58; H,
4.18. Found: C, 63.43; H, 4.21.
(d, J ) 5.2 Hz, 1H), 4.13 (d, J ) 4.8 Hz, 1H), 3.82 (s, 3H), 1.62
(s, 3H), 1.42 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.9, 157.5,
130.7, 121.1, 114.5, 68.5, 64.4, 58.7, 55.8, 53.7, 29.1, 28.2; IR
(thin film) 1760 cm-1 (â-lactam CdO). HRMS (CI, isobutane)
calcd for C14H16NO2SBr (M + 1) 342.0159, obsd 342.0078.
1
31a : 0.121 g (98%); colorless crystals (mp 99-100 °C); H
NMR (400 MHz, CDCl3) δ 7.65 (d, J ) 8.8 Hz, 2H), 7.50-7.36
(m, 5H), 6.92 (d, J ) 8.8 Hz, 2H), 5.32 (s, 1H), 3.80 (s, 3H),
2.93 (q, J ) 5.8 Hz, 2H), 1.38 (t, J ) 5.8 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 162.7, 157.9, 150.9, 134.4, 130.6, 130.2, 129.5,
129.2, 121.6, 114.8, 72.9, 69.6, 55.9, 53.9, 25.6, 14.9; IR (thin
film) 1760 cm-1 (â-lactam CdO). Anal. Calcd for C20H18
NO2S2I: C, 48.49; H, 3.66. Found: C, 48.24; H, 3.33.
-
31b: 0.098 g (73%); colorless crystalline solid (mp 105-108
°C); 1H NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 10H), 4.80
(d, J ) 15.6 Hz, 1H), 4.71 (s, 1H), 4.60 (d, J ) 15.6 Hz, 1H),
2.85-2.80 (m, 2H), 1.28 (t, J ) 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 165.6, 148.9, 136.0, 134.3, 132.0, 130.5, 129.5, 129.2,
129.0, 128.9, 128.8, 82.4, 70.2, 45.6, 25.3, 14.9; IR (thin film)
1752 cm-1 (â-lactam CdO). HRMS (CI, isobutane) calcd for
P r oced u r e for Ha locycliza tion Rea ction s. To a solution
of â-lactam 38a (1.25 g, 5.1 mmol) in CH2Cl2 (50 mL) is added
I2 (1.28 g, 5.1 mmol). The mixture is stirred while heating at
reflux for 4 h. After cooling to RT, the reaction mixture is
poured into 5% aqueous Na2S2O3 (25 mL) and stirred until
the purple coloration of iodine has dissipated. The aqueous
mixture is extracted with CH2Cl2 (3 × 50 mL), and the
combined organic layers are dried over MgSO4, filtered, and
evaporated. Flash chromatography of the crude mixture
affords 1.28 g (72%) of 39a as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 7.46-7.37 (m, 5H), 5.17 (overlapping signal,
2H), 3.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 182.9, 148.2,
131.5, 130.5, 129.5, 129.4, 90.0, 78.0, 69.7, 60.8; IR (thin film)
1790 cm-1 (â-lactam CdO). HRMS (CI, isobutane) calcd for
C
20H18NOS2I (M + 1) 479.9949, obsd 479.9940. Anal. Calcd
for C20H18NOS2I: C, 50.11; H, 3.78. Found: C, 49.87; H, 3.95.
31c: 0.132 g (92%); colorless oil; 1H NMR (400 MHz, CDCl3)
δ 7.37-7.26 (m, 5H), 4.78 (d, J ) 15.6 Hz, 2H), 4.56 (s, 1H),
4.40 (d, J ) 15.6 Hz, 2H), 2.82-2.70 (m, 2H), 1.25 (t, J ) 6.8
Hz, 3H), 0.97 (t, J ) 8.0 Hz, 9H), 0.85 (q, J ) 8.0 Hz, 6H); 13
C
NMR (75 MHz, CDCl3) δ 166.0, 150.5, 136.0, 129.5, 129.0,
128.5, 84.4, 79.0, 74.8, 45.8, 25.0, 15.0, 7.8, 3.1; IR (thin film)
1753 cm-1 (â-lactam CdO). HRMS (CI, isobutane) calcd for
C
12H10NO2SI (M + 1) 359.9553, obsd 359.9578. Anal. Calcd
C20H28NOS2SiI (M + 1) 518.0498, obsd 518.0517. Anal. Calcd
for C12H10NO2SI: C, 40.13; H, 2.81. Found: C, 40.51; H, 2.98.
An analogous procedure was used to prepare the following
bicyclic â-lactams.
for C20H28NOS2SiI: C, 46.41; H, 5.45. Found: 46.50; H, 5.38.
34: 0.098 g (4:1 mixture, 100%); colorless oil; 1H NMR (400
MHz, CDCl3) δ 7.38-7.34 (m, 5H, both isomers), 4.90 (d, J )
15.6 Hz, 1H, R-isomer), 4.75 (d, J ) 15.6 Hz, 1H, â-isomer),
4.31 (d, J ) 15.6 Hz, 1H, R-isomer), 4.29 (d, J ) 4.8 Hz, 1H,
â-isomer), 4.18 (d, J ) 15.6 Hz, 1H, â-isomer), 4.16 (d, J ) 4.8
Hz, 1H, â-isomer), 4.15 (partially obscured d, J ) 4.8 Hz,1H,
R-isomer), 4.08 (d, J ) 4.8 Hz, 1H, R-isomer), 2.71 (q, J ) 5.9
Hz, 2H, both isomers), 1.64 (s, 3H, both isomers), 1.39 (s, 3H,
both isomers), 1.24 (t, J ) 5.9 Hz, 3H, both isomers); 13C NMR
(75 MHz, CDCl3) (â-isomer only) δ 165.7, 135.2, 129.5, 129.1,
128.7, 75.5, 71.7, 64.0, 60.1, 45.5, 27.5, 27.1, 26.2, 14.4; IR (thin
film) 1755 cm-1 (â-lactam CdO). HRMS (CI, isobutane) calcd
for C16H20NOS2Br (M + 1) 386.0243, obsd 386.0237. Anal.
Calcd for C16H20NOS2Br: C, 49.74; H, 5.22. Found, C, 49.77;
H, 5.50.
39b: 0.054 g (84%); colorless solid (mp 217-218 °C); 1H
NMR (400 MHz, CDCl3) δ 7.86 (dd, J ) 2.9, 4.9 Hz, 2H), 7.75
(dd, J ) 2.9, 4.9 Hz, 2H), 7.47-7.38 (m, 5H), 6.10 (d, J ) 4.8
Hz, 2H), 5.30 (d, J ) 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 178.8, 166.9, 147.7, 135.4, 132.0, 131.5, 130.6, 129.5, 129.0,
124.9, 76.2, 69.6, 62.9; IR (thin film) 1790 cm-1 (â-lactam Cd
O). HRMS (CI, isobutane) calcd for C19H11N2O3SI (M + 1)
474.9611, obsd 474.9595. Anal. Calcd for C19H11N2O3SI: C,
48.12; H, 2.34. Found: C, 48.28; H, 2.18.
47: 0.111 g (95% yield based on the estimated amount of
45 in a 1:10 mixture of 43:45); colorless solid (mp 124-126
°C); 1H NMR (500 MHz, CDCl3) δ 7.50-7.24 (m, 10H), 4.85
(d, J ) 2.3 Hz, 1H), 4.29 (d, J ) 2.3 Hz, 1H), 3.98 (AB m, 2H);
13C NMR (125 MHz, CDCl3) δ 180.1, 146.9, 137.1, 131.1, 131.0,
130.0, 129.6, 129.5, 129.5, 128.4, 82.4, 73.0, 62.1, 36.8; IR (thin
53a (one isomer, 54%): colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.39-7.29 (m, 5H), 5.88 (d, J ) 4.9 Hz, 1H), 4.82 (d,
J ) 3.6 Hz, 1H), 4.10 (dd, J ) 4.9, 3.6 Hz, 1H), 3.57 (s, 3H),
2.17 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.2, 168.8, 141.7,
138.6, 130.6, 130.0, 129.4, 86.7, 86.4, 67.9, 60.1, 58.1, 21.6; IR
(thin film) 1780 (â-lactam CdO), 1750 cm-1 (acetate CdO).
HRMS (CI, isobutane) calcd for C15H14NO4SI (M + 1) 431.9763,
obsd 431.9778. Anal. Calcd for C15H14NO4SI: C, 41.78; H,
3.27. Found: C, 41.99; H, 3.11.
film) 1780 cm-1 (â-lactam CdO); Anal. Calcd for C18H14
NOS2I: C, 47.90; H, 3.13. Found: C, 47.66; H, 3.30.
-
The following compounds were prepared in a similar man-
ner, except that the halogenation reactions were conducted at
room temperature.
18: 0.066 g (approximately 95% based on the cis:trans ratio
of â-lactams 17); colorless crystals (mp 150-151 °C); 1H NMR
(400 MHz, CDCl3) δ 7.72-7.39 (m, 7H), 6.90 (d, J ) 8.8 Hz,
2H), 5.59 (d, J ) 4.8 Hz, 1H), 5.02 (d, J ) 4.8 Hz, 1H), 3.79 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 164.1, 157.9, 149.8, 137.5,
134.8, 130.6, 130.0, 129.4, 122.9, 121.6, 114.6, 76.0, 70.5, 56.0;
IR (thin film) 1750 cm-1 (â-lactam CdO). Anal. Calcd for
53b: (major isomer, 61%); colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.92 (dd, J ) 2.9, 4.9 Hz, 2H), 7.78 (dd, J ) 2.9, 4.9
Hz, 2H), 7.45-7.38 (m, 5H), 5.76 (d, J ) 4.9 Hz, 1H), 5.60 (d,
J ) 6.8 Hz, 1H), 4.15 (dd, J ) 4.9, 6.8 Hz, 1H), 2.04 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 170.3, 168.0, 163.7, 139.5, 138.2,
135.1, 132.2, 130.7, 130.1, 129.4, 124.4, 85.2, 67.2, 59.7, 57.3,
20.9; IR (thin film) 1780 cm-1 (â-lactam CdO). HRMS (CI,
isobutane) calcd for C22H17N2O5SI (M + 1) 546.9825, obsd
546.9791. Anal. Calcd for C22H17N2O5SI: C, 48.37; H, 2.77.
Found: 48.11; H, 3.02.
P r oced u r e for th e Su lfon yla tion of â-La cta m s. To a
stirred suspension of 39a (335 mg, 0.675 mmol) and KH2PO4-
Na2HPO4 (pH 7.8, 20 mL) in CH2Cl2 (50 mL) at room
temperature is added in one portion m-chloroperoxybenzoic
acid (1.50 g, 50-60%, ∼4.2 mmol). The mixture is stirred for
12 h and poured into a 5% aqueous NaHSO3 solution (60 mL).
The mixture is stirred for 8 h until the layers become
separated, and the organic layer is washed with a 5% aqueous
NaHCO3 solution (50 mL). The aqueous layer is extracted
with CH2Cl2 (2 × 30 mL), and the combined organic layers
C
18H14NO2SI: C, 49.67; H, 3.24. Found: 49.77; H, 3.33.
21: 0.057 g (approximately 90% based on the cis:trans ratio
of â-lactams 20); colorless oil. Data for major isomer: 1H NMR
(400 MHz, CDCl3) δ 7.49 (d, J ) 8.8 Hz, 2H), 6.90 (d, J ) 8.8
Hz, 2H), 5.02 (dd, J ) 4.0, 4.8 Hz, 1H), 4.73 (d, J ) 4.8 Hz,
1H), 4.37 (d, J ) 4.0 Hz, 1H), 3.79 (s, 3H), 1.58 (s, 3H), 1.47
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.9, 157.2, 129.4, 119.2,
115.2, 69.0, 62.7, 60.8, 55.8, 55.6, 28.7, 28.0; IR (thin film) 1760
cm-1 (â-lactam CdO); MS (relative intensity) 342 (M + 1, 94),
264 (33), 232 (32), 190 (52), 167 (14), 149 (52), 129 (33), 113
(52). HRMS (CI, isobutane) calcd for C14H16NO2SBr (M + 1)
342.0159, obsd 342.0151. Anal. Calcd for C14H16NO2SBr: C,
49.13; H, 4.71. Found: 49.50; H, 4.38. Data for minor
isomer: 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J ) 8.8 Hz, 2H),
6.90 (d, J ) 8.8 Hz, 2H), 5.15 (dd, J ) 4.8, 5.2 Hz, 1H), 4.52

8916 J . Org. Chem., Vol. 63, No. 24, 1998
Ren et al.
are dried over anhydrous MgSO4 and evaporated. Flash
chromatography of the crude mixture affords 326 mg (82%) of
sulfone 58a as a white solid (decomposed upon heating): H
NMR (400 MHz, CDCl3) δ 7.62-7.48 (m, 5H), 5.61 (d, J ) 5.0
Hz, 2H), 5.23 (d, J ) 5.0 Hz, 1H), 3.63 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 150.0, 145.4, 131.9, 129.9, 129.8, 126.8, 101.4,
96.0, 67.9, 57.8; IR (thin film) 1801 cm-1 (â-lactam CdO).
HRMS (CI, isobutane) calcd for C12H10NO4SI (M + 1) 391.9451,
obsd 391.9460. Anal. Calcd for C12H10NO4SI: C, 36.84; H,
2.58. Found, C, 33.70; H, 2.68.
1H), 3.82 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 165.0, 157.7,
147.4, 133.1, 130.5, 129.6, 129.4, 129.0, 128.9, 128.6, 126.3,
123.6, 114.2, 68.7, 55.4, 54.0; IR (film) 1750 cm-1 (â-lactam
CdO). HRMS (CI, isobutane) m/z calcd for C20H17NO2S (M +
1) 336.1054, found 336.1061. Anal. Calcd for C20H17NO2S: C,
71.62; H, 5.11. Found: C, 71.45; H, 4.87.
1
A similar procedure was used to prepare â-lactam deriva-
tives 74b and 74c.
74b: 0.075 g (80%); pale yellow oil; 1H NMR (500 MHz,
CDCl3) δ 7.37 (app s, 4H), 7.30-7.26 (m, 3H), 6.77 (d, J ) 9.0
Hz, 2H), 6.20 (dd, J ) 1.5, 3.5 Hz, 1H), 6.01 (d, J ) 5.5 Hz,
1H), 5.70 (d, J ) 3.5 Hz, 1H), 5.03 (d, J ) 5.5 Hz, 1H), 3.82 (d,
J ) 1.5 Hz, 1H), 3.76 (s, 3H); 13C NMR (125 MHz) δ 164.8,
157.5, 149.7, 141.2, 134.3, 130.8, 130.0, 129.4, 129.1, 121.3,
118.5, 114.9, 114.7, 112.5, 108.9, 70.4, 56.1, 55.0; IR (film) 1750
cm-1 (â-lactam CdO). HRMS (CI, isobutane) m/z calcd for
56a : 0.028 g (86%); colorless solid (95-96 °C); 1H NMR (400
MHz, CDCl3) δ 7.56-7.48 (m, 7H), 6.95 (d, J ) 8.8 Hz, 2H),
5.81 (s, 1H), 3.82 (s, 3H), 3.75-3.62 (m, 2H), 1.62 (t, J ) 6.8
Hz, 3H); 13C NMR (90 MHz, CDCl3) δ 159.2, 153.4, 152.3,
132.1, 129.9, 129.7, 127.9, 127.0, 123.1, 114.9, 100.0, 87.7, 63.0,
55.8, 49.8, 5.0; IR (thin film) 1780 cm-1 (â-lactam CdO).
HRMS (CI, isobutane) calcd for C20H18NO6S2I (M + 1) 559.9694,
obsd 559.9708. Anal. Calcd for C20H18NO6S2I: C, 42.94; H,
3.24. Found, C, 42.66; H, 3.47.
C
22H17NO3S (M + 1) 376.1003, found 376.0993. Anal. Calcd
for C22H17NO3S: C, 70.38; H, 4.56. Found: C, 70.65; H, 4.83.
74c: 0.120 g (74%); colorless oil; 1H NMR (400 MHz, CDCl3)
δ 7.30-7.18 (m, 13H), 6.61 (s, 1H), 5.81 (d, J ) 5.6 Hz, 1H),
5.09 (d, J ) 5.6 Hz, 1H), 3.60 (s, 3H), 2.76 (s, 3H); IR (film)
1750 cm-1 (â-lactam CdO). HRMS (CI, isobutane) m/z calcd
for C27H22N2O2S (M + 1) 439.1475, found 439.1480. Anal.
Calcd for C27H22N2O2S: C, 73.95; H, 5.06. Found: C, 73.65;
H, 4.83.
1
56b: 0.012 g (45%); colorless crystals (mp 192-194 °C); H
NMR (400 MHz, CDCl3) δ 7.50-7.30 (m, 10H), 5.19 (s, 1H),
5.04 (d, J ) 15.6 Hz, 1H), 4.56 (d, J ) 15.6 Hz, 1H), 3.60 (q, J
) 6.8 Hz, 2H), 1.62 (t, J ) 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 156.0, 154.2, 134.0, 131.8, 131.5, 129.9, 129.8, 128.6,
128.5, 99.9, 92.0, 68.2, 48.4, 48.3, 47.1, 5.5; IR (thin film) 1785
cm-1 (â-lactam CdO); CIMS (relative intensity) 544 (M + 1,
8), 420 (70), 395 (100), 379 (98), 294 (69), 262 (45), 253 (68),
220 (69), 133 (21). Anal. Calcd for C20H18NO5S2I: C, 44.21;
H, 3.34. Found, C, 44.46; H, 3.37.
P a lla d iu m -Ca ta lyzed Ester ifica tion of â-La cta m Io-
d id es 18, 31a , a n d 56a . To a stirred solution of 18 (0.260 g,
0.62 mmol) in a mixture of anhydrous DMF (10 mL) and
anhydrous methanol (5 mL) in a heavy-walled pressure bottle
were added Pd2dba3 (0.026 g, 0.028 mmol) and PPh3 (0.013 g,
0.05 mmol). The mixture was stirred for 5 min. A flow of
carbon monoxide was passed through the pressure bottle for
5 min, the valve was closed, and the bottle was pressurized
with CO to 55 psi. The reaction mixture was stirred for 4 d
at RT (or for 24 h at 50-56 °C). Water (75 mL) was added,
and the mixture was extracted with Et2O (3 × 25 mL). The
combined organic layers were dried over MgSO4 and evapo-
rated. Flash chromatography of the crude product afforded
0.169 g (75%) of 75 as a pale yellow oil: 1H NMR (400 MHz,
CDCl3) δ 7.55 (d, J ) 8.8 Hz, 2H), 7.40-7.37 (m, 5H), 6.87 (d,
J ) 8.8 Hz, 2H), 6.00 (d, J ) 5.9 Hz, 1H), 4.98 (d, J ) 5.9 Hz,
1H), 3.79 (s, 3H), 3.51 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
166.2, 164.2, 163.8, 157.5, 133.6, 130.7, 128.8, 128.7, 120.9,
118.8, 114.9, 69.5, 66.6, 56.2, 55.2, 52.1, 34.8, 23.1, 16.0, 14.8;
IR (film) 1750 (â-lactam CdO), 1730 cm-1 (ester CdO). HRMS
(CI, isobutane) m/z calcd for C20H17NO4S (M + 1) 368.0952,
found 368.0954. Anal. Calcd for C20H17NO4S: C, 65.38; H,
4.66. Found: C, 65.31; H, 4.83.
56c: 0.053 g (72%); colorless oil; 1H NMR (400 MHz, CDCl3)
δ 7.40-7.32 (m, 5H), 5.15 (s, 1H), 4.91 (d, J ) 15.0 Hz, 1H),
4.58 (d, J ) 15.0 Hz, 1H), 3.66 (td, J ) 6.8, 10.8 Hz, 1H), 3.53
(td, J ) 6.8, 10.8 Hz, 1H), 1.58 (t, J ) 6.8 Hz, 3H), 0.08 (m, 15
H); 13C NMR (75 MHz, CDCl3) δ 152.5, 141.5, 131.1, 127.8,
127.6, 127.1, 100.5, 87.4, 62.2, 47.8, 44.9, 4.7, 3.9, 3.0; IR (thin
film) 1785 cm-1 (â-lactam CdO). Anal. Calcd for C20H28
NO5S2SiI: C, 41.31; H, 4.85. Found: C, 41.27; H, 4.51.
-
57: 0.053 g (1:4 mixture of R:â isomers, 73%). Data for major
isomer: white crystals (mp 145-148 °C); 1H NMR (400 MHz,
CDCl3) δ 7.40-7.35 (m, 5H), 4.78 (d, J ) 15.6 Hz, 1H), 4.67
(d, J ) 5.9 Hz, 1H), 4.33 (d, J ) 15.6 Hz, 1H), 4.15 (d, J ) 5.9
Hz, 1H), 3.62 (q, J ) 4.9 Hz, 2H), 1.55 (s, 3H), 1.50 (t, J ) 4.9
Hz, 3H), 1.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.1, 132.6,
129.9, 129.8, 129.6, 91.6, 75.8, 61.4, 51.4, 48.0, 46.5, 19.4, 18.4,
4.4; IR (thin film) 1775 cm-1 (â-lactam CdO). Data for minor
isomer: 1H NMR (400 MHz, CDCl3) δ 7.42-7.36 (m, 5H), 5.04
(d, J ) 15.0 Hz, 1H), 4.73 (d, J ) 3.9 Hz, 1H), 4.38 (d, J )
15.0 Hz, 1H), 4.30 (d, J ) 3.9 Hz, 1H), 3.59 (td, J ) 6.8, 10.8
Hz, 1H), 3.44 (td, J ) 6.8, 10.8 Hz, 1H), 1.76 (s, 3H), 1.58 (t,
J ) 6.8 Hz, 3H), 1.50 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
156.4, 132.8, 129.9, 129.8, 129.7, 89.0, 67.5, 57.0, 50.9, 50.0,
47.9, 22.3, 21.8, 5.2; IR (thin film) 1775 cm-1 (â-lactam CdO).
Anal. Calcd for C16H20NO5S2Br: C, 42.67; H, 4.48. Found:
C, 42.77; H, 4.61.
A similar procedure was used to prepare compounds 76-
78.
76: 0.150 g (73%); colorless oil; 1H NMR (250 MHz, CDCl3)
δ 7.59-7.24 (m, 7H), 6.86 (d, J ) 8.8 Hz, 2H), 6.01 (d, J ) 5.5
Hz, 1H), 5.82 (ddd, J ) 5.5, 11.1, 22.7 Hz, 1H), 5.61 (ddd, J )
5.5, 10.8, 22.7 Hz, 1 H), 4.94-5.20 (AB m, 2H), 4.67 (d, J )
5.5 Hz, 1H), 4.43 (d, J ) 5.6 Hz, 1H), 3.80 (s, 3H); IR (film)
1750 (â-lactam CdO), 1730 cm-1 (ester CdO). HRMS (CI,
isobutane) m/z calcd for C22H19O4NS (M+) 393.1030, found
393.1040. Anal. Calcd for C22H19NO4S: C, 67.16; H, 4.87.
Found: C, 67.50; H, 4.65.
58b: 0.051 g (87%); colorless crystals (decomposed upon
heating); 1H NMR (400 MHz, CDCl3) δ 7.92-7.78 (m, 4H),
7.53-7.46 (m, 5H), 5.89 (d, J ) 6.1 Hz, 1H), 5.62 (d, J ) 6.1
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 168.3, 167.6, 166.5,
158.6, 135.7, 131.1, 129.8, 129.4, 125.1, 124.9, 99.5, 75.6, 57.4;
IR (thin film) 1795 cm-1 (â-lactam CdO). Anal. Calcd for
77: 0.093 g (90%); pale yellow oil; 1H NMR (400 MHz, CDCl3)
δ 7.55 (d, J ) 9.0 Hz, 2H), 7.37-7.35 (m, 5H), 6.87 (d, J ) 9.0
Hz, 2H), 5.73 (s, 1H), 3.80 (s, 3H), 3.54 (s, 3H), 2.96 (AB m,
2H), 1.37 (t, J ) 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
166.6, 164.0, 162.8, 157.7, 133.2, 130.9, 130.3, 129.0, 128.7,
121.1, 118.0, 115.0, 71.6, 56.2, 54.2, 52.3, 25.8, 15.6; IR (film)
1755 (â-lactam CdO), 1730 cm-1 (ester CdO). HRMS (CI,
isobutane) m/z calcd for C22H21NO4S2 (M + 1) 428.0985, found
428.0990. Anal. Calcd for C22H21NO4S2: C, 61.80; H, 4.95.
Found: C, 62.11; H, 5.13.
C
19H11N2O5SI: C, 45.08; H, 2.19. Found: C, 45.37. H, 2.43.
Stille Cr oss-Cou p lin g Rea ction s of Or ga n osta n n a n es
w ith â-La cta m 18. To a stirred solution of â-lactam 18 (0.120
g, 0.28 mmol) in anhydrous DMF (10 mL) at RT were added
Pd2dba3 (0.010 g, 0.011 mmol) and PPh3 (0.005 g, 0.02 mmol).
Tributylvinyltin (0.100 g, 0.31 mmol) was added, and the
mixture was stirred under N2 for 12 h. Water (50 mL) was
added, and the mixture was extracted with Et2O (3 × 15 mL).
The combined organic layers were dried over MgSO4, filtered,
and evaporated. The crude oil was purified by flash chroma-
tography on silica gel to provide 0.085 g (80%) of 74a as a
transparent oil: 1H NMR (360 MHz, CDCl3) δ 7.41-7.38
(overlapping m, 7H), 6.86 (d, J ) 8.9 Hz, 2H), 6.52 (dd, J )
11.1, 17.6 Hz, 1H), 5.76 (d, J ) 5.3 Hz, 1H), 5.15 (d, J ) 17.6
Hz, 1H), 5.06 (d, J ) 11.1 Hz, 1H), 4.97 (dd, J ) 1.4, 5.3 Hz,
78: 0.121 g (73%); white crystals (mp 154-157 °C); 1H NMR
(360 MHz, CDCl3) δ 7.37-7.35 (m, 7H), 6.87 (d, J ) 9.2 Hz,
2H), 6.03 (s, 1H), 3.81 (s, 3H), 3.78 (overlapping m, 2H), 3.65
(s, 3H), 1.64 (t, J ) 7.2 Hz, 3H); 13C NMR (90 MHz, CDCl3) δ
170.0, 162.6, 158.0, 151.0, 133.8, 131.2, 130.2, 129.8, 129.3,
128.7, 128.3, 121.2, 114.4, 62.7, 55.5, 52.9, 48.2, 14.2; IR (film)

Nonconventionally Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 63, No. 24, 1998 8917
1780 (â-lactam CdO), 1730 cm-1 (ester CdO). Anal. Calcd
for C22H21NO8S2: C, 53.76; H, 4.31. Found: C, 53.65; H, 4.33.
P a lla d iu m -Ca ta lyzed Ca r boxyla tion of â-La cta m Ac-
id s 18, 31a , a n d 56a . To a stirred solution of 18 (0.120 g,
0.28 mmol) in a mixture of DMF (10 mL) and H2O (0.1 mL) in
a heavy glass pressure bottle were added Pd2dba3 (0.014 g,
0.015 mmol) and PPh3 (0.005 g, 0.02 mmol). The mixture was
stirred for 10 min and purged with CO for 5 min. The valve
was closed, and the bottle was pressurized with CO (55 psi).
The reaction mixture was stirred for 5 days at RT. Water (50
mL) was added, and the mixture was extracted with EtOAc
(3 × 15 mL). The combined organic layers were dried over
MgSO4 and evaporated. Flash chromatography afforded 0.065
g (65%) of 79 as a colorless oil: 1H NMR (500 MHz, DMSO-
d6) 12.6 (br s, 1H), 7.53 (d, J ) 7.5 Hz, 2H), 7.38 (s, 5H), 6.95
(d, J ) 7.5 Hz, 2H), 6.00 (d, J ) 3.5 Hz, 1H), 5.31 (d, J ) 3.5
Hz, 1H), 3.74 (s, 3H); 1H NMR (400 MHz, CDCl3) δ 7.41-7.38
(m, 7H), 6.82 (d, J ) 9.5 Hz, 2H), 5.99 (d, J ) 5.5 Hz, 1H),
5.10 (d, J ) 5.5 Hz, 1H), 3.77 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 164.1, 163.3, 161.7, 156.1, 133.0, 130.0, 129.7,
128.1, 128.0, 119.8, 119.4, 114.2, 69.1, 55.3, 54.0; IR (film) 1750
(â-lactam CdO), 1725 cm-1 (carboxylic acid CdO). Anal.
Calcd for C19H15NO4S: C, 64.58; H, 4.28. Found: C, 64.48;
H, 4.38.
2H), 7.97-7.83 (m, 3H), 7.18-7.08 (m, 2H), 6.63 and 6.40 (br
s, 1H each), 5.60 and 5.28 (d, J ) 5.6 Hz, 1H each), 4.59 and
4.15 (d,
J
) 5.2 Hz, 1H each). Anal. Calcd for
C38H24N4O6S2I2: C, 48.02; H, 2.54. Found: C, 47.67; H, 2.82.
86: 0.063 g (95%) from 58a as a colorless solid (mp 150-
153 °C); 1H NMR (360 MHz, CDCl3) δ 7.69-7.41 (m, 5H), 5.46
(br H, 1H), 5.19 (d, J ) 3.9 Hz, 1H), 4.39 (d, J ) 3.9 Hz, 1H),
3.45 (s, 3H); 13C NMR (125 MHz) δ 171.7, 163.3, 151.7, 132.4,
132.2, 130.5, 129.7, 128.7, 104.4, 59.1. HRMS (CI, isobutane)
m/z calcd for C12H12NO5SI (M + 1) 409.9556, found 409.9573.
Anal. Calcd for C12H12NO5SI: C, 35.22; H, 2.96. Found: C,
35.60; H, 3.21.
Testin g for An tim icr obia l Su scep tibilities. The follow-
ing strains of bacteria were used to test our â-lactam com-
pounds for antimicrobial susceptibilities: Enterobacter cloacae
USF510 (environmental isolate), Escherichia coli USF503
(ATCC 23590), Klebsiella pneumoniae USF512, Pseudomonas
aeruginosa USF620 (ATCC 15442), Salmonella typhimurium
USF515 (obtained from University of South Florida Medical
Clinic), Serratia marcescens USF519 (ATCC 29634), Staphy-
lococcus aureus USF525 (ATCC 25923), Vibrio cholerae
USF1018 (biotype El Tor Inaba, cholera toxin positive, CDC
E5906), and Vibrio cholerae USF1019 (biotype El Tor Ogawa,
cholera toxin negative, CDC 1074-78). Bacteria were streaked
for isolation onto tryptic soy agar (TSA) plates (REMEL,
Lenexa, KS). An isolated colony from each plate was removed
with a sterile swab and streaked onto a TSA plate. Sterile
1/4-in.-diameter Bacto concentration disks (Difco Laboratories,
Detroit, MI) were impregnated with 20 µL of the test com-
pound dissolved in DMSO (or DMSO, as a control), dried for
A similar procedure was used to prepare compounds 80 and
81.
80: 0.068 g (75%); colorless oil: 1H NMR (500 MHz, CDCl3)
δ 7.58 (d, J ) 8.9 Hz, 2H), 7.39-7.37 (m, 5H), 6.84 (d, J ) 9.1
Hz, 2H), 5.69 (s, 1H), 3.80 (s, 3H), 2.94 (AB m, 2H), 1.38 (t, J
) 7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.3, 167.7,
162.6, 157.7, 132.8, 131.2, 130.3, 129.2, 128.9, 121.0, 116.9,
115.0, 76.7, 71.4, 56.2, 25.9, 15.6; IR (film) 1755 (â-lactam Cd
3 h in
a biohazard safety cabinet, and placed onto the
inoculated TSA plates.59 The inoculated TSA plates with
the compound-impregnated disks were incubated for 24 h at
37 °C, and antimicrobial susceptibilities were determined by
measuring the zone of growth inhibition around each disk.60
O), 1725 cm-1 (carboxylic acid CdO). Anal. Calcd for C21H19
-
NO4S2: C, 61.00; H, 4.63. Found: C, 61.16; H, 4.58.
In addition to compound 80, thioester 82 was also ob-
1
tained: 0.013 g (10%) as a colorless oil; H NMR (400 MHz,
CDCl3) δ 7.52 (d, J ) 9.6 Hz, 2H), 7.39-7.37 (m, 5H), 6.85 (d,
J ) 8.4 Hz, 2H), 5.77 (s, 1H), 3.78 (s, 3H), 2.93 (AB m, 2H),
2.75 (q, J ) 7.2 Hz, 2H), 1.38 (t, J ) 7.2 Hz, 3H), 1.09 (t, J )
7.2 Ηz, 3H); 13C NMR (125 MHz) δ 188.1, 162.8, 162.6, 157.7,
132.5, 131.2, 130.4, 129.4, 129.3, 127.8, 121.1, 114.9, 56.2, 54.2,
25.8, 24.6, 15.6, 15.2; IR (film) 1758 cm-1 (â-lactam CdO).
HRMS (CI, isobutane) m/z calcd for C23H23NO3S3 (M + 1)
458.0913, found 458.1065. Anal. Calcd for C23H23NO3S3: C,
60.36; H, 5.07. Found: C, 60.35; H, 5.30.
Ack n ow led gm en t. We express our sincere thanks
and appreciation to the donors of the Petroleum Re-
search Fund, administered by the American Chemical
Society, for financial support of this research project.
This work was funded, in part, by the University of
South Florida Research and Creative Scholarship Grant
Program. E.T. and J .G. would like to acknowledge the
NATO for an International Travel Grant. H.S. thanks
the Government of the People’s Republic of China for
providing support as a visiting scientist, and the De-
partment of Chemistry at Tsinghua University for a
faculty leave. The authors would also like to give special
thanks to Professor J iali Gao and Dr. J oseph Pavelites
(SUNY Buffalo) for their technical assistance with the
semiempirical calculations.
81: 0.099 g (72%); colorless oil; 1H NMR (360 MHz, CDCl3)
δ 7.66-7.30 (m, 7H), 1H), 6.89 (d, J ) 8.8 Hz, 2H), 5.88 (s,
1H), 3.79 (s, 3H), 3.75 (overlapping m, 1H), 3.60 (m, 1H), 1.61
(t, J ) 7.6 Ηz, 3H); IR (film) 1785 (â-lactam CdO), 1725 cm-1
(carboxylic acid CdO). Anal. Calcd for C21H19NO8S2: C, 52.82;
H, 4.01. Found: C, 52.59; H, 3.84.
Attempted carboxylation of 39b and 58a under similar
conditions led to the formation of 84 and 86, respectively.
84: 0.099 g (1:1 mixture of diastereomers, 93%) from 39b
as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.92-7.78 (m,
2H), 7.30 (m, 3H), 6.95 and 6.89 (d, J ) 3.6 Hz, 2H each), 6.06
and 5.85 (br s, 1H each), 5.51 (d, J ) 5.6 Hz, 1H) and 5.34 (d,
J ) 4.4 Hz, 1H), 4.45 (d, J ) 5.6 Hz, 1H) and 4.26 (d, J ) 5.6
Hz, 1H); 1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J ) 8.4 Hz,
J O9811219
(59) Blumenthal, R. M.; Raeder, R.; Takemoto, C. D.; Freimer, E.
H. Antimicrob. Agents Chemother. 1983, 24, 61.
(60) Bauer, A. W.; Kirby, W. M. M.; Sheris, J . C.; Turck, M. Am. J .
Clin. Path. 1966, 45, 493.