Stereoselective synthesis of fused bicyclic β-lactams through radical cyclization of enyne-2-azetidinones

Article abstract of DOI:10.1021/jo9823994

A convenient, stereoselective entry to racemic and enantiomerically pure fused bicyclic β-lactams has been developed that involves the radical- mediated cycloisomerization of easily available monocyclic enyne-β-lactams as the key synthetic step. These compounds are obtained provided that an activated double bond is present as a radical acceptor. In the absence of this condition, new forms of reactivity were observed, including C3-C4 bond cleavage of the β-lactam ring to yield tetrahydropyridine derivatives and 1,5-radical translocation to yield new bicyclic derivatives. Some simple transformations were tested on representative examples of the different types of bicyclic systems prepared to demonstrate their potential as intermediates in the preparation of other differently functionalized systems.

Full text of DOI:10.1021/jo9823994

J . Org. Chem. 1999, 64, 5377-5387
5377
Ster eoselective Syn th esis of F u sed Bicyclic â-La cta m s th r ou gh
Ra d ica l Cycliza tion of En yn e-2-a zetid in on es1
Benito Alcaide,* Ignacio M. Rodr´ıguez-Campos, J ulia´n Rodr´ıguez-Lo´pez, and
Alberto Rodr´ıguez-Vicente
Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad Complutense,
28040-Madrid, Spain
Received December 8, 1998
A convenient, stereoselective entry to racemic and enantiomerically pure fused bicyclic â-lactams
has been developed that involves the radical-mediated cycloisomerization of easily available
monocyclic enyne-â-lactams as the key synthetic step. These compounds are obtained provided
that an activated double bond is present as a radical acceptor. In the absence of this condition,
new forms of reactivity were observed, including C3-C4 bond cleavage of the â-lactam ring to
yield tetrahydropyridine derivatives and 1,5-radical translocation to yield new bicyclic derivatives.
Some simple transformations were tested on representative examples of the different types of bicyclic
systems prepared to demonstrate their potential as intermediates in the preparation of other
differently functionalized systems.
In tr od u ction
eration of the radical by some of the standard methodolo-
gies, followed by its intramolecular capture by a radical
acceptor attached to the 2-azetidinone nucleus, results
in ring closure. There is an isolated example of the use
of a terminal alkyne as a proradical center in the
synthesis of a bicyclic â-lactam, namely, the elegant
preparation of some of these compounds from 4-alkynyl-
â-lactams by a one-pot, four step, sequential reaction
reported by Bachi.9
In our ongoing project directed at the development of
efficient routes to prepare bi- and polycyclic â-lactam
systems,10 we recently introduced enyne-2-azetidinones
as starting materials for the synthesis of fused bicyclic
and tricyclic â-lactams by using radical cyclization1 and
the Pauson-Khand reaction,11 respectively. We report
here a general study into the use of terminal alkynes
tethered to a 2-azetidinone ring as proradical centers.1
The presence of a double bond as a radical acceptor in
the appropriate position allows access to different fused
bicyclic â-lactams (Scheme 1). Furthermore, different
cyclization products, as well as fragmentation com-
Synthetic methodologies based on free radical cycliza-
tion reactions have experienced an impressive growth
and are the focus of extensive studies. This wide-ranging
research has been fostered by the mild, neutral reaction
conditions required for radical generation and the fact
that, by a combination of stereoelectronic and molecular
orbital effects, radical cyclizations occur, in general, with
high degrees of both regio- and stereocontrol.2 Since the
pioneering work by Stork,3 the radical cycloisomerization
of doubly unsaturated precursors, especially 1,6-dienes
or enynes, promoted by an external radical source, is a
powerful entry to complex carbocyclic and heterocyclic
systems.4 The increased interest in the preparation of
novel bi- and polycyclic â-lactam systems,5 a result of the
necessity to combat the increasing resistance of bacteria
to classical antibiotics,6 makes these compounds attrac-
tive targets for synthetic approaches based on radical
cyclization. However, although the radical methodology
has been widely used to prepare fused bicyclic â-lactams,
radical cyclization of 2-azetidinone-bridged dienes or
enynes has been limited to the cyclization of N-(2-bromo-
2-propen-1-yl)-4-vinyl-2-azetidinone to yield both carbap-
enam and carbacepham derivatives.7 Most of the radical
routes to fused bicyclic â-lactams make use of halogeno-,
thio-, and seleno-derivatives as proradical centers.8 Gen-
(4) For other representative examples of radical cyclizations from
dienes or enyne systems using different radical promoters, see the
following. Cyclizations using R3SnH: (a) Hanessian, S.; Ninkovic, S.
J . Org. Chem. 1996, 61, 5418. (b) Nishida, M.; Ueyama, E.; Hayashi,
H.; Ohtake, Y.; Yamaura, Y.; Yanaginuma, E.; Yonemitsu, O.; Nishida,
A.; Kawahara, N. J . Am. Chem. Soc. 1994, 116, 6455. (c) J anardhanam,
S.; Balakumar, A.; Rajagopalan, K. J . Chem. Soc., Perkin Trans. 1
1994, 551. (d) J anardhanam, S.; Shanmugam, P.; Rajagopalan, K. J .
Org. Chem. 1993, 58, 7782. (e) Hanessian, S.; Le´ger, R. J . Am. Chem.
Soc. 1992, 114, 3115. (f) Enholm, E. J .; Kinter, K. S. J . Am. Chem.
Soc. 1991, 113, 7784. (g) Knight, K. S.; Waymouth, R. M. J . Am. Chem.
Soc. 1991, 113, 6268. (h) Yang, Z.-Y.; Burton, D. J . J . Org. Chem. 1991,
56, 5125. (i) Stork, G.; Reynolds, M. E. J . Am. Chem. Soc. 1988, 110,
6911. Cyclizations using silicon hydrides: (j) Kopping, B.; Chatgilia-
loglu, C.; Zehnder, M.; Giese, B. J . Org. Chem. 1992, 57, 3994.
Cyclizations using sulfur- and phosphorus-centered radicals: (k)
Brumwell, J . E.; Simpkins, N. S.; Terret, N. K. Tetrahedron 1994, 50,
13533. (l) Brumwell, J . E.; Simpkins, N. S.; Terret, N. K. Tetrahedron
Lett. 1993, 34, 1215. (m) Brumwell, J . E.; Simpkins, N. S.; Terret, N.
K. Tetrahedron Lett. 1993, 34, 1219. (n) Chuang, C.-P. Tetrahedron
Lett. 1992, 33, 6311. (o) Serra, A. C.; da Silva Correa, C. M. M.; do
Vale, M. L. C. Tetrahedron 1991, 47, 9463. (p) De Riggi, I.; Surzur,
J .-M.; Bertrand, M. P.; Archavlis, A.; Faure, R. Tetrahedron 1990, 46,
5285. (q) Chuang, C.-P. Synlett 1990, 527. (r) Broka, C. A.; Reichert,
D. E. C. Tetrahedron Lett. 1987, 28, 1503. (s) Padwa, A. Nimmesgern,
H.; Wong, G. S. K. J . Org. Chem. 1985, 50, 5620.
(1) For a preliminary communication describing part of this work,
see: Alcaide, B.; Benito, J . L.; Rodr´ıguez-Campos, I. M.; Rodr´ıguez-
Lo´pez, J .; Rodr´ıguez-Vicente, A.; Sierra, M. A.; Garc´ıa-Granda, S.;
Gut´ıerrez-Rodr´ıguez, A. Tetrahedron: Asymmetry 1995, 6, 1055.
(2) For leading references, see: (a) Beckwith, A. L. J . Tetrahedron
1981, 37, 3073. (b) Hart, D. J . Science 1984, 223, 883. (c) Giese, B.
Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds;
Pergamon Press: New York, 1986. (d) Ramaiah, Tetrahedron 1987,
43, 3541. (e) Curran, D. P. Synthesis 1988, 717 and 489. (f) J asperse,
C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237. (g)
Motherwell, W. B.: Crich, D. Free Radical Chain Reactions in Organic
Synthesis; Academic Press: London, 1991. (h) Curran, D. P. In
Comprehesive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford,
1992; Vol. 4, Chapter 4.2. (i) Curran, D. P.; Porter, N. A.; Giese, B. In
Stereochemistry of Radical Reactions; VCH Publishers: New York,
1996. (g) Malacria, M. Chem. Rev. 1996, 96, 289.
(3) (a) Stork, G.; Mook R., J r. J . Am. Chem. Soc. 1987, 109, 2829.
(b) Stork, G.; Mook R., J r. J . Am. Chem. Soc. 1983, 105, 3720. (c) Stork,
G.; Baine, N. H., J r. J . Am. Chem. Soc. 1982, 104, 2321.
10.1021/jo9823994 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

5378 J . Org. Chem., Vol. 64, No. 15, 1999
Alcaide et al.
Sch em e 1
Ch a r t 1
pounds, derived from modes of reaction other than those
mentioned above will be also presented. â-Lactams of
types I and II have the carbapenam (n ) 1) or carba-
(5) For an exhaustive revision of cyclization methodologies to
prepare bicyclic â-lactams, see: (a) Kant, J .; Walker, D. G. In The
Organic Chemistry of â-Lactams; Georg, G. I., Ed.; VCH Publishers:
New York, 1993; Chapter 3. Recent examples related to the synthesis
of trinem and trinem derivatives: (b) Camerini, R.; Donati, D.;
Marchioro, C.; Mazzoni, A.; Pachera, R.; Panunzio, M. Tetrahedron:
Asymmetry 1997, 8, 15. (d) Di Fabio, R.; Rossi, T.; Thomas, R. J .
Tetrahedron Lett. 1997, 38, 3587. (e) Marchioro, C.; Pentassuglia, G.;
Perboni, A.; Donati, D. J . Chem. Soc., Perkin Trans. 1 1997, 463. (f)
Rossi, T.; Marchiro, C.; Paio, A.; Thomas, R. J .; Zarantonello, P. J .
Org. Chem. 1997, 62, 1653. (d) Hanessian, S.; Griffin, A. M.; Rozema,
M. J . BioMed. Chem. Lett. 1997, 7, 1857. (e) Guiron, C.; Rossi, T.;
Thomas, R. J . Tetrahedron Lett. 1997, 20, 3569. (f) Hanessian, S.;
Rozema, M. J . J . Am. Chem. Soc. 1996, 118, 9884. For recent examples
on the synthesis of new, different types of polycyclic â-lactams, see:
(g) Martel, S. R.; Wisedale, R.; Gallagher, L. D.; Mahon, F.; Badbury,
R. H.; Hales, N. J . J . Am. Chem. Soc. 1997, 119, 2309. (h) Planchenault,
D.; Wisedale, R.; Gallagher, T.; Hales, N. J . J . Org. Chem. 1997, 62,
3438. (i) Elliot, R. L.; Nicholson, N. H.; Peaker, F. E.; Takle, A. K.;
Richardson, C. M.; Tyler, J . W.; White, J .; Pearson, M. J .; Eggleston,
D. S.; Haltiwanger, R. C. J . Org. Chem. 1997, 62, 4998. (j) Sakya, S.
M.; Strohmeyer, T. W.; Lang, S. A.; Lin, Y.-I. Tetrahedron Lett. 1997,
38, 5913. (k) Annibalc, A. D.; Pesce, A.; Resta, S.; Irogolo, C. T.
Tetrahedron 1997, 53, 13129. (l) Banik, B. K.; Gottumukkala, V.;
Manhas, M. S.; Bose, A. K. Tetrahedron Lett. 1996, 37, 1363. (m)
Chuansheng, N.; Pettersson, T.; Miller, M. J . J . Org. Chem. 1996, 61,
1014. (n) Crocker, P. J .; Miller, M. J . J . Org. Chem. 1995, 60, 6176. (o)
Gilchrist, T. L.; Graham, K. Tetrahedron Lett. 1995, 47, 8693. (p)
Hanessian, S.; Reddy, B. G. BioMed. Chem. Lett. 1994, 19, 2285.
(6) For excellent articles on the bacterian resistance to the commonly
used antibiotics, see: (a) Hook, V. Chem. Br. 1997, 33, 34. (b) Niccolai,
D.; Tarsi, L.; Thomas, R. J . Chem. Commun. 1997, 2333. (c) Spratt, B.
G. Science 1994, 264, 388-393.
cepham (n ) 2) ring systems,12 whereas compounds of
type III have an unusual carbapenam structure, with the
lactam group moved out from the point of ring fusion.13
This structural feature is present in cispentacin, a potent
antifungal antibiotic.14
Resu lts a n d Discu ssion
To assess the scope and limitations of the radical
cyclization of enyne-â-lactams to access different fused
bicyclic â-lactams, a wide variety of substrates was pre-
pared (Chart 1, Scheme 2). In all cases, the four-mem-
bered ring was constructed by the standard Staudinger
ketene-imine cyclization (Scheme 2).15 Enyne-â-lactams
(7) (a) Knight, J .; Parsons, P. J .; Southgate, R. J . Chem. Soc., Chem.
Commun. 1986, 78. (b) Knight, J .; Parsons, P. J . J . Chem. Soc., Perkin
Trans. 1 1987, 1237.
(12) The interest in carbapenams and carbacepham rests in their
structural similarity to the carbapenem- and carbacephem-type com-
pounds, which are highly active, broad-spectrum antibiotics with
â-lactamase resistance. For reviews on the synthesis of carbapenem,
see: (a) Ratcliffe, R. W.; Albers-Schonberg, G. In Chemistry and Biology
of â-Lactam Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic
Press: New York, 1982, Vol. 2, p 227. (b) Kametani, T.; Fukumoto, K.;
Ihara, M. Heterocycles 1982, 17, 463. (c) Nagahara, T.; Kametani, T.
Heterocycles 1987, 25, 729. (d) Georg, G. I. In Studies in Natural
Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1989;
Vol. 4, p 431. (e) Palomo, C. In Recent Progress in the Chemical
Synthesis of Antibiotics; Springer-Verlag: Berlin-Heidelberg, 1990; p
565. (f) Berks, A. H. Tetrahedron 1996, 52, 331. For recent reviews
on the synthesis of carbacephems: (g) Cooper, R. D. G. In The
Chemistry of â-Lactams; Page, M. I., Ed.; Chapman and Hall: Lon-
don, 1992; Chapter 8. (h) Kant, J .; Walker, D. G. In The Organic
Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: Weinheim, 1993;
Chapter 3, p 121.
(13) Bicyclic â-lactams having the lactam group adjacent to the ring
fusion point have been reported. See, for example: (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 and references therein.
(14) For a recent asymmetric synthesis of cispentacin, see: (a)
Davies, S. G.; Ichihara, O.; Walters, I. A. S. Synlett 1993, 461. (b)
Davies, S. G.; Ichihara, O.; Lenoir, I.; Walters, I. A. S. J . Chem. Soc.,
Perkin Trans. 1 1994, 1411 and references therein.
(8) See, for example: (a) Kant, J .; Walker, D. G. In The Organic
Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: Weinheim, 1993;
Chapter 3, pp 159-167. (b) Bachi, M. D. In Recent Advances in the
Chemistry of â-Lactam Antibiotics; Bentley, P. H., Southgate, R., Eds.;
Spec. Pub. No. 70; R. Soc. Chem.: London, 1989; Chapter 6. (c) Bachi,
M. D.; Hoornaert, C. Tetrahedron Lett. 1981, 22, 2689. (d) Bachi, M.
D.; Frolow, F.; Hoornaert, C. J . Org. Chem. 1983, 48, 1841. (e)
Beckwith, A. L. J .; Boate, D. R. Tetrahedron Lett. 1985, 26, 1761. (f)
Kametani, T.; Chu, Sh.-D.; Itoh, A.; Maeda, S.; Honda, T. J . Org. Chem.
1988, 53, 2683. (d) Anaya, J .; Barton, D. H. R.; Gero, S. D.; Grande,
M.; Mart´ın, N.; Tachdijian, C. Angew. Chem., Int. Ed. Engl. 1993, 32,
867. (e) Bachi, M. D.; Bar-Ner, N. BioMed. Chem. Lett. 1993, 3, 2439
and references therein.
(9) Bosch, E.; Bachi, M. D. J . Org. Chem. 1993, 58, 5581.
(10) See, for example: (a) Alcaide, B.; Rodr´ıguez-Vicente, A. Tetra-
hedron Lett. 1998, 39, 6589. (b) Alcaide, B.; Polanco, C.; Sa´ez, E.; Sierra,
M. A. J . Org. Chem. 1996, 61, 7125. (c) Alcaide, B.; Rodr´ıguez-Vicente,
A.; Sierra, M. A. Tetrahedron: Asymmetry 1996, 7, 2203. (d) Alcaide,
B.; Pe´rez-Castells, J .; Sa´nchez-Vigo, B.; Sierra, M. A. BioMed. Chem.
Lett. 1993, 3, 2369.
(11) (a) Alcaide, B.; Polanco, C.; Sierra, M. A. J . Org. Chem. 1998,
63, 6786. (b) Alcaide, B.; Polanco, C.; Sierra, M. A. Tetrahedron Lett.
1996, 37, 6901.

Synthesis of Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 64, No. 15, 1999 5379
Sch em e 2
4a and 4b were transformed into E/Z mixtures of enyne-
â-lactams 4d and 4e, respectively, by dihydroxylation
(OsO4/Me3NO), diol cleavage (NaIO4/MeOH/H2O), and
Wittig olefination of the aldehyde 9. Finally, 3-propargyl-
4-alkenyl-â-lactams 5 were obtained by Wittig olefination
of racemic 4-formyl â-lactams 10. Aldehydes 10 were
prepared according to our previously reported one-pot
synthesis for related compounds,22 by reaction of 4-pen-
tynoyl chloride and the glyoxal diimine derived from
p-anisidine (Scheme 2).23
2-Azetidinones 1-5 were reacted with Bu3SnH (TBTH)
or Ph3SnH (TPTH) in boiling benzene and in the presence
of AIBN. Reactions were carried out under standard
dilution conditions; syringe pumps or other high dilution
techniques were not required. Vinyltin carbapenams 11
and 12 and 3,4-fused bicyclic â-lactams 13 were obtained
as the exclusive reaction products when the vinyl group
had phenyl or CO2Me groups attached (Scheme 3, Table
1, entries 1-8, 10-12, 14-19).24 In these cases, the 5-exo-
trig products were formed as mixtures of two diastereo-
mers, which are epimers at the newly formed chiral
center. Products with a carbacepham structure, arising
from 6-endo-trig cyclization, or reduced compounds, from
hydrostannylation of the triple bond, were not detected
in any case. Each diastereoisomer was stereochemically
homogeneous at the tin-substituted double bond. The
configuration of the double bond is Z for compounds 11
and 12 and E for compounds 13 (see below). Purification
of these compounds was performed easily and efficiently
by flash chromatography to give good to excellent yields.
The structure of compounds 11-13 was determined by
standard NMR techniques. In all cases, the stereochem-
istry of the 2-azetidinone ring present in the starting
material remained unaltered during the cyclization
process. It was established by the value of coupling
constants of the original H3-H4 protons (J ) 3.9-5.4
1, 3, and 4a -c were obtained directly in both the racemic
(compounds 3 and 4) and enantiopure forms (compounds
1) when enyne imines were used as substrates. 2-Azeti-
dinones 1a -c were obtained as single cis-diastereomers
(de > 95%) from (+)-(S)-(4-phenyl-2-oxo-1,3-oxazolidin-
3-yl)acetic acid and the corresponding imine using dichlo-
rophenyl phosphate as the condensating agent.16 2-Aze-
tidinones 6, derived from D-glyceraldehyde acetonide
imines, were used as synthetic intermediates to prepare
enantiomerically pure enyne â-lactams 2. Thus, optically
pure compounds 2a -e were prepared as E/ Z mixtures
in good to excellent yields from enantiomerically pure (+)-
(3R,4S,4′S)-2-azetidinones 617 by standard acetonide
hydrolysis, followed by cleavage of the diols 7 (NaIO4/
MeOH/H2O),18 and Wittig olefination of the resulting
â-lactam aldehyde 8.19 This sequence yielded only moder-
ate yields of 4-vinyl-â-lactams 2f and 2g. Good yields of
these compounds could be obtained by using the Corey-
Hopkins method.20 Thus, after acetonide hydrolysis, diols
7 were sequentially reacted with thiocarbonyldiimidazole
(TCDI) in boiling THF and trimethyl phosphite21 to form
the vinyl derivatives 2f and 2g. N-Allyl-2-azetidinones
(17) The cis/ trans-selectivity observed for compounds 1-6 was
expected according to the current model for the Stau¨dinger reaction.
(a) Arrieta, A.; Lecea, B.; Coss´ıo, F. P. J . Org. Chem. 1998, 63, 5869.
(b) Palomo, C.; Aizpurua, J . M.; Mielgo, A.; Linden, A. J . Org. Chem.
1996, 61, 9186. (c) Cossio, F. P.; Arrieta, A.; Lecea, B.; Ugalde, J . M.
J . Am. Chem. Soc. 1994, 116, 2085. (d) Hegedus, L. S.; Montgomery,
J .; Narukawa, Y.; Snustad, D. C. J . Am. Chem. Soc. 1991, 113, 5784.
This model accounts for the 3R,4S stereochemistry of 2-azetidinones
derived from D-glyceraldehyde. For an experimental study on the
synthesis of 2-azetidinones derived from D- and L-glyceraldehyde
acetonide imines, see: (e) Niu, Ch.; Miller, M. J . Tetrahedron Lett.
1995, 36, 497. (f) Hubschwerlen, C.; Schmid, G. Helv. Chim. Acta 1983,
66, 2206. (g) Welch, J . T.; Araki, K.; Kawecki, R.; Wichtowski, J . A. J .
Org. Chem. 1993, 58, 2454. (h) Wagle, D. R.; Garai, C.; Chiang, J .;
Monteleone, M. G.; Kurys, B. E.; Strohmeyer, T. W.; Hedge, V. R.;
Manhas, M. S.; Bose, A. K. J . Org. Chem. 1988, 53, 4227 and references
therein.
(18) Alcaide, B.; Esteban, G.; Mart´ın-Cantalejo, Y.; Plumet, J .;
Rodr´ıguez-Lo´pez, J .; Monge, A.; Pe´rez-Garc´ıa, V. J . Org. Chem. 1994,
59, 7994.
(19) â-Lactam aldehydes
8 were obtained and used for Wittig
olefination as mixtures with their methoxyhemiacetals. However, these
mixtures can be easily transformed to the free aldehydes by azeotropic
distillation using a Dean-Stark apparatus.
(15) (a) Staudinger, M. Liebigs Ann. Chem. 1907, 356, 51. For recent
reviews on the asymmetric ketene-imine approach to â-lactams, see:
(b) Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of
â-Lactams; Georg, G. I., Ed.; VCH: Weinheim, 1993; Chapter 3, p 295.
(c) van der Steen, F. H.; van Koten, G. Tetrahedron 1991, 47, 7503.
(d) Cooper, R. D. G.; Daugherty, B. W.; Boyd, D. B. Pure Appl. Chem.
1987, 59, 485. For comprehensive general reviews of the synthesis of
â-lactams, see: (e) Koppel, G. A. In Small Ring Heterocycles; Hassner,
A., Ed.; Wiley: New York, 1983; Vol. 42, p 219. (f) Ghosez, L.;
Marchand-Brynaert, J . In Comprehensive Organic Synthesis; Trost,
B., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 85. (g)
DeKimpe, N. In Comprehensive Heterocyclic Chemistry II; Padwa, A.,
Ed.; Elsevier: Oxford, 1996; Vol. 1B, p 507.
(20) Corey, E. J .; Snider, D. B. J . Am. Chem. Soc. 1972, 94, 2459.
(21) Horton, D.; Turner, W. N. Tetrahedron Lett. 1964, 36, 2531.
(22) Alcaide, B.; Mart´ın-Cantalejo, Y.; Pe´rez-Castells, J .; Rodr´ıguez-
Lo´pez, J .; Sierra, M. A.; Monge, A.; Pe´rez-Garc´ıa, V. J . Org. Chem.
1992, 57, 5921.
(23) Other apparently more staightforward methods, i.e., the
Staudinger reaction between pentynoyl chloride and the imine derived
from p-anisidine and cinnamaldehyde, failed to produce the corre-
sponding â-lactam 5a .
(24) It is notable that radical cyclization to give bicyclic compounds
11-13 occurs under standard conditions, whereas related processes
developed to prepare bicyclic â-lactams do not occur except in high
dilution conditions. See, for example ref 9. In our case, good yields of
products were obtained even when working in the absence of solvent
(neat conditions).
(16) Arrieta, A.; Lecea, B.; Coss´ıo, F. P.; Palomo, C. J . Org. Chem.
1988, 53, 3784-3791.

5380 J . Org. Chem., Vol. 64, No. 15, 1999
Alcaide et al.
Sch em e 3
this compound. It is therefore reasonable to assume that
the configuration at C1 of all major isomers of compounds
11 is 1R,5R,6S for Evans oxazolidine derivatives 11a ,b
and 1S,5S,6R for carbapenams 11c-h derived from
glyceraldehyde acetonide (Chart 2). The slight variation
in the diastereomer ratio in the formation of compounds
11, which is independent of the nature of R1and R2,
supports this hypothesis. It also seems reasonable that
the stereocenter determining the configuration of the new
chiral center is that at the C4 â-lactam carbon of the
starting 2-azetidinones.
The relative stereochemistry of racemic compounds
12b,c was determined by NOE experiments carried out
on the major isomer of compound 12c. Irradiation of the
vinyl proton at 6.05 ppm resulted in an 11% and 3%
enhancement of the signals of the CH2CO2Me group and
H2 respectively, which is in agreement with a Z stereo-
chemistry for the double bond. However, no enhancement
was observed when H5 was irradiated. This is compatible
with an anti stereochemistry between H2 and H5.
Therefore, a 2S*,5S*,6R* configuration was assigned to
the major isomer of compounds 12b,c. Finally, the
stereochemistry of compounds 13 was determined from
the coupling constants between H4-H5 of the bicyclic
system. Thus, coupling between H4-H5 was not observed
for the major isomers of compounds 13, while vicinal
coupling constants J 4,5 were 4.5-4.8 Hz for the minor
isomers. These values are in good agreement with a syn-
stereochemistry for the major isomers and an anti-
disposition for the minor isomers, as reported for related
systems.18 Chart 2 shows the stereochemistry data for
compounds 11-13.
Ta ble 1. Syn th esis of Sta n n yl Bicyclic â-La cta m s 11-13
fr om En yn e-2-a zetid in on es 1-5
yield, (%)a
anti/
entry substrateb,c
R1
Ph
Ph
Ph
Ph
CO2Me PhO Bu
CO2Me PhO Ph
CO2Me BnO Bu
CH3
H
R2
R3 product synd anti
syn
1
2
1a
1a
2a
2b
2c
2c
2d
2e
2g
S-Oxe Bu
S-Oxe Ph
PhO Bu
BnO Bu
11a
11b
11c
11d
11e
11f
11g
11h
11i
88:12 80 (95) 11
90:10 72 (96)
81:19 40 (70)
82:18 35 (50)
f
5
5
3
4
5
6
85:15 58 (80) 12
85:15 30 (63)
81:19 37 (60)
82:18 25 (47)
f
f
f
7
8
9
PhO Ph
BnO Ph
Ch a r t 2
77:23
g
10
11
12
13
14
15
16
17
18
19
tr a n s-3c Ph
tr a n s-3c Ph
tr a n s-3d Ph
i-Pr
i-Pr
allyl Ph
PhO Ph
Bu
Ph
11j
11k
11l
12a
12b
12c
13a
13b
13c
13d
90:10 50 (60)
90:10 71 (86)
90:10 50 (92)
f
f
f
4a
4d
4e
5a
5a
5b
5b
H
80:20
g
CO2Me PhO Bu
CO2Me BnO Bu
68:32 57 (70)
62:38 56 (70)
f
f
Ph
Ph
PMPh Bu
PMPh Ph
78:22
88:12
55:45
55:45
(47)
(72)
(78)
(64)
CO2Me PMPh Bu
CO2Me PMPh Ph
a
In all cases, complete transformation to the bicyclic products
was observed by 1H NMR spectroscopy. Yields without parenthesis
are for isolated products purified by column chromatography; those
within parentheses are for the chromatographically homogeneous
mixture of the two inseparable isomers. With the exception of 2a ,
partial destannylation and/or decomposition was observed after
b
chromatographic workup. Compounds 1a and 2a -f were used
as optically pure materials with the configuration indicated in
Chart 1. The remaining substrates 3 and 4 were used as racemic
mixtures of pure trans or cis diastereomers. c Except for enyne
â-lactams 1a and trans-3c,d (E-isomers), E/Z mixtures of isomers
were used for the remaining substrates (see Experimental Section).
The synthesis of carbapenams and related bicyclic
â-lactams discussed above makes use of R,â-unsaturated
esters or styryl groups as radical acceptors. This ensures
a 5-exo-trig ring closure and an enhancement of the rate
of the radical cyclization due to the electron-withdrawing
nature of the acceptor. Furthermore, the diastereomer
ratio was remarkably independent of the stereochemistry
of the radical acceptor double bond. To confirm this
statement, an E/Z mixture (85:15) of 2-azetidinone 2c and
its pure Z-isomer were reacted independently with
d
Isomer ratio (epimers at C1) were determined by integration of
well-resolved signals in the 1H NMR spectra of crude reaction
mixtures. e S-Ox ) (S)-4-phenyl-2-oxo-1,3-oxazolidin-3-yl. f At-
tempts to isolate the minor (syn) isomer were unsuccessful in this
g
case. The cyclization product was obtained along with a hy-
drostannylated product as a chromatographically inseparable
h
mixture. PMP ) 4-Methoxyphenyl.
Hz for the cis-isomers; J ) 0-1.5 Hz for the trans-
isomers). The stereochemistry of the new chiral center
of compounds 11 was determined from an X-ray diffrac-
tion analysis carried out on compound anti-29a , the
destannylation product of the major isomer of carbap-
enam 11a (see Table 2 and Scheme 10).25 This analysis
allows the assignment of a 1R,5R,6S configuration for
(25) Major isomers of carbapenams 11 show a J 1,5 ) 7.4-8.4 Hz,
and the minor isomers have a J 1,5 ) 8.0-8.7 Hz. Therefore, the relative
configuration at C1 could not be unambiguously established from NMR
data.

Synthesis of Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 64, No. 15, 1999 5381
TBTH/AIBN in refluxing benzene. The diastereomeric
ratio of the carbapenam obtained (11e) (85:15) was
identical in both cases. In contrast, products derived from
hydrostannylation of the triple bond were the major
components obtained in the reaction of compounds 2e-g
and cis-3a ,b with TBTH. However, tetrahydropyridines
14a ,b were isolated in the reactions of â-lactams 3a and
2e. In fact, compound 14b was the major product in the
reaction of 2e with TBTH (Scheme 4). Separation and
purification of tetrahydropyridines 14 was difficult, and
the overall yields were low. In contrast, bicyclic carbap-
enams 11h ,i and 12a were obtained from compounds 2e,
2g and 4a , respectively (Table 1), albeit in low yields,
when TPTH was used instead of TBTH.
analogous reaction of compound 1c gave a complex
reaction mixture with the corresponding hydrostanny-
lated derivative as the main component. In addition, the
reaction of azaenyne derivative 18 with TBTH/AIBN
behaves in a similar fashion to give the corresponding
amino bicyclic â-lactam 19, in 59% isolated yield, as a
mixture of isomers (78:22) (Scheme 6).27
Sch em e 6
Sch em e 4
Interestingly, reaction of compound 4b with both
TBTH and TPTH gave new compounds, which were
identified as bicyclic â-lactams 15a ,b, in high yield (85%
and 62%, respectively, as isolated products) and as single
diastereomers. Clearly, this compound represents a new
mode of cyclization of enyne-â-lactams in a process that
is general for 4-alkynyl-2-azetidinones having a benzyl-
oxy group at C3. This is demonstrated by the preparation
of compounds 15a -d in good yields from 3-alkynyl-2-
azetidinones 4a and 16a ,b (Scheme 5). However, this
reaction is restricted to this type of substrate, i.e., with
a benzyloxy group at C3. Other substituents at this
position, such as methoxy and acetoxy, led only to the
corresponding hydrostannylated derivatives. The relative
stereochemistry of compounds 15a -d was determined
from the vicinal coupling constants, as discussed above
for compounds 13. No coupling between H4-H5 was
observed, which is indicative of an anti relative disposi-
tion, whereas a J 3,4 coupling (4.3-4.8 Hz) arises from a
relative syn configuration at these centers in compounds
13. Aza-analogues of bicycles 15 have been reported
recently to be active against the class C â-lactamases.26
Reaction with other cyclization promoters was also
studied. Thus, Ph2PH and TsBr were reacted with
â-lactam 1a in boiling benzene and in the presence of
AIBN.4k-s In both cases, a smooth conversion to carbap-
enams 20 and 21 was observed (Scheme 7). Reaction with
Ph2PH led to the formation of carbapenam 20a as a single
diastereomer and in excellent yield as crude product.
Compound 20a was readily transformed to its phosphine
oxide 20b during the chromatographic purification pro-
cess. Bromo-sulfone 21a was obtained as a mixture of
isomers (90:10) which are epimers at the newly formed
halogenated exocyclic chiral center. Reduction of the
bromo-sulfones 19a (TBTH/AIBN/C6H6/∆) gave bicyclic
sulfone 21b, thus confirming the epimeric nature of
isomers of 21a at the halogenated stereocenter. A
Sch em e 7
Sch em e 5
Extension of this approach to higher homologue bicyclic
systems was tested on â-lactams 1b,c. Carbacepham
derivatives 17a ,b were obtained from â-lactam 1b by
reaction with TBTH and TPTH, respectively, as single
diastereomers in good yields (Scheme 6). However, the

5382 J . Org. Chem., Vol. 64, No. 15, 1999
Alcaide et al.
particularly noteworthy aspect of this approach is the
total stereoselectivity observed in the formation of the
C1 stereocenter in these cases in comparison with that
obtained using the tin approach.
translocation generates a new, stable, benzyl radical 28,
which evolves to the final products 15 through a 5-exo-
trig cyclization process onto the tin-substituted double
bond (Scheme 9). The complete selectivity observed in
the formation of compounds 15 should be due to the
preference of the radical intermediate 28 for the confor-
mation depicted in Scheme 9 for these cyclizations. This
fact is well documented for analogous cyclizations on
1-substituted 5-hexen-1-yl radicals, in which the cis-
cyclopentane is always obtained.2,31
The results discussed above may be understood in
terms of the reaction pathway presented in Scheme 8 for
the synthesis of bicycles 11. The first step should be the
addition of the in situ-generated stannyl radical to the
triple bond to form the key intermediate vinyl radical 22.
For activated double bonds, a 5-exo-trig ring closure
occurs, yielding the expected carbapenam products 11-
13. Substitution at the acceptor carbon atom or nonac-
tivated double bonds essentially results in the inhibi-
tion of the cyclization process, even for activated double
bonds. In these cases, reduction products are obtained
as the main components of the reaction mixtures. Fur-
thermore, formation of tetrahydropyridines 14 may be
explained by a homolytic C3-C4 bond cleavage in the
2-azetidinone nucleus of intermediates 24 or 25 to form
radical intermediates 26, which are precursors of com-
pounds 14. This interesting process, which is an example
of a radical C3-C4 bond breakage in the â-lactam ring,28
is closely related to the cyclobutylcarbinyl radical cleav-
age, a useful methodology for the synthesis of medium-
sized rings.29 In our case, the driving force for the
cleavage may be the stability of the captodative radical
26 (Scheme 8, R3 ) PhO) together with the strain in the
â-lactam ring.
Sch em e 9
Sch em e 8
Finally, some simple transformations were carried out
on selected bicyclic â-lactams 11, 13, and 17 (Scheme 10,
Table 2) to test their viability as intermediates in the
synthesis of other differently functionalized fused bicyclic
systems. Thus, protiodestannylation (TsOH/Cl2CH2, rt)
of some representative compounds, 11, 13, and 17,
afforded the corresponding methylene bicyclic-â-lactams
29, 30, and 33, respectively. Reaction of major isomers
of compounds 11a and 11j with iodine (I2/Cl2CH2, rt)
resulted in the corresponding vinyl iodides 31a ,b, re-
spectively. However, ozonolysis of compound 29a oc-
curred without problems to give oxo-derivative 32. Oxo-
derivatives related to 32 have been used as advanced
intermediates in the synthesis of active carbapenem
antibiotics.12a-f
(26) (a) Angehrn, P.; Gubernator, K.; Gutknecht, E. M.; Heinze-
Krauss, I.; Hubschwerlen, C.; Kania, M.; Page, M. G. P.; Specklin,
J . L. 35th Intescience Conference on Antimicrobial Agents and Che-
motherapy; Program and Abstracts, F147, 1995. (b) Charnas, R.;
Gubernator, K.; Heinze, I.; Hubschwerlen, C. Eur. Pat. 0508234A2,
1992.
(27) For the related free radical cycloisomerization of alkyne-
tethered oxime ethers, see: (a) Marco-Contelles, J . L.; Destabel, Ch.;
Gallego, P.; Chiara, J . L.; Bernabe´, M. J . Org. Chem. 1996, 61, 1354.
(b) Booth, S. E.; J enkins, P. R.; Swain, C. J .; Sweeney, J . B. J . Chem.
Soc., Perkin Trans. 1 1994, 3499. (c) Enholm, E. J .; Burroff, J . A.;
J aramillo, L. M. Tetrahedron Lett. 1990, 31, 3927.
(28) For a related ionic C3-C4 ring fragmentation, see: Alcaide,
B.; Mart´ın-Cantalejo, Y.; Rodr´ıguez-Lo´pez, J .; Sierra, M. A. J . Org.
Chem. 1993, 58, 4767-4770.
(29) See, for example: (a) Crimmings, M. T.; Huang, S.; Guise-
Zabacki, L. E. Tetrahedron Lett. 1996, 37, 6519. (b) Horwell, D. C.;
Morrell, A. I.; Roberts, E. Tetrahedron Lett. 1995, 36, 459-460 and
references therein.
(30) For related examples on translocation of radical sites by
intramolecular 1,5-hydrogen atom transfer, see: (a) Curran, D. P.; Kim,
D.; Liu, H.; Shen, W. J . Am. Chem. Soc. 1988, 110, 5900. (b) Snieckus,
V.; Cuevas, J .-C.; Sloan, C. P.; Liu, H.; Curran, D. J . Am. Chem. Soc.
1990, 112, 896. (c) Burke, S.; J ung, K. W. Tetrahedron Lett. 1994, 35,
5837. (d) Parsons, P. J .; Caddick, S. Tetrahedron 1994, 50, 13523.
(31) (a) Spellmeyer, D. C.; Houk, K. N. J . Org. Chem. 1987, 52, 959.
(b) Reference 2.
Formation of compounds 15a -d from 3-benzyloxy-â-
lactams 4b and 16a ,b may be explained by 1,5-radical
translocation of the initially formed vinyl radicals 27.9,30
In fact, in the absence of a good radical acceptor, this

Synthesis of Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 64, No. 15, 1999 5383
tynamine,33 2,3-O-(isopropylidene)-D-glyceraldehyde,34 (S)-
phenylglycinol,35 (S)-4-phenyl-2-oxazolidinone,36 (S)-(4-phenyl-
2-oxo-oxazolidin-3-yl)-acetic acid,37 and N,N-di(p-methoxyphen-
yl)glyoxaldiimine.38
Sch em e 10
Gen er a l P r oced u r es for th e Syn th esis of 1-P r op a r gyl-
2-a zetid in on es 1, 3, 4a -c, a n d 16. Meth od A. A solution of
the corresponding aldehyde (10 mmol) and amine (10 mmol)
in CH2Cl2 (10 mL) was stirred overnight at room temperature
over MgSO4. Then, the MgSO4 was filtered off and washed
with an additional 15 mL of CH2Cl2, and the resulting solution
was cooled at 0 °C under argon. Et3N (4.16 mL, 30 mmol) and
the corresponding acid or acid chloride (15 mmol) (and PhOP-
(O)Cl2, only when (S)-4-phenyl-2-oxo-1,3-oxazolidin-3-yl-acetic
acid is used, 2.25 mL, 15 mmol) were successively added, and
the mixture was stirred overnight at room temperature.
Finally, it was diluted with CH2Cl2, washed with 5% HCl (×1),
H2O (×2), and dried (MgSO4). After filtration and evaporation
of the solvent under reduced pressure, the crude products were
purified by column chromatography (silica gel; hexanes/EtAcO
mixtures). Meth od B. A solution of the corresponding alde-
hyde (30 mmol) and amine (30 mmol) in Et2O (200 mL) was
stirred at room temperature over MgSO4 (35 g). After 6 h, the
mixture was filtered, and 100 mL of toluene was added. The
resulting solution was concentrated under reduced pressure
to 100 mL. To this solution of imine was added Et3N (90 mmol)
and a solution of the corresponding acid chloride (36 mmol)
in toluene (25 mL). The resulting mixture was stirred over-
night at room temperature and partitioned between H2O and
CH2Cl2 (3 × 50 mL). Finally, the organic layer was washed
with brine and dried (MgSO4). After filtration and evaporation
of the solvent under reduced pressure, the crude products were
purified by column chromatography (silica gel; hexanes/EtAcO
mixtures). Representative examples for the preparation of
enyne-2-azetidinones following both methods follow.39
(+)-(3S,4R)-3-[(S)-4-P h en yl-2-oxo-1,3-oxa zolid in -3-yl]-
1-p r op a r gyl-4-(E)-styr yl-2-a zetid in on e (1a ). Meth od A.
From E-cinnamaldehyde (1.32 g, 10 mmol), propargylamine
(0.55 g, 10 mmol), (S)-4-phenyl-2-oxo-1,3-oxazolidin-3-yl-acetic
acid (3.31 g, 15 mmol), and PhOP(O)Cl2 (2.25 mL, 15 mmol),
2.86 g of the title compound was obtained. Flash chromatog-
raphy (silica gel; hexanes/EtAcO, 2:1). Yield: 77%. White
needles. Mp: 183-184 °C. [R]D ) +107 (c ) 2, CHCl3). 1H NMR
(CDCl3) δ: 2.18 (t, 1H, J ) 2.7 Hz), 3.70 (dd, 1H, J ) 2.7, 18.0
Hz), 4.18 (dd, 1H, J ) 7.2, 8.7 Hz), 4.29 (dd, 1H, J ) 2.7, 18.0
Hz), 4.47-4.53 (m, 2H), 4.62 (t, 1H, J ) 8.7 Hz), 4.85 (dd, 1H,
J ) 7.2, 8.7 Hz), 6.05 (dd, 1H, J ) 8.4, 15.9 Hz), 6.68 (d, 1H,
J ) 15.9 Hz), 7.31-7.44 (m, 10H). 13C NMR (CDCl3) δ: 163.1,
157.7, 137.6, 137.0, 135.7, 129.7, 129.6, 128.8, 128.7, 127.8,
127.0, 122.7, 76.4 72.9, 70.8, 63.0, 61.1, 60.3, 30.1. IR (KBr) ν:
3250, 1750, 1655. Anal. Calcd for C23H20N2O3: C, 74.18; H,
5.41; N, 7.52. Found: C, 73.84; H, 5.52; N, 7.48.
Ta ble 2. Syn th esis of Bicyclic â-La cta m s 29-32
substrate
anti-11a Ph
syn-11a Ph
anti-11b Ph
anti-11c Ph
anti-11d Ph
R1
R2
R3
X
Y
product yield, (%)a
S-Oxb Bu
S-Oxb Bu
S-Oxb Ph
PhO
BnO
H
H
H
H
H
H
H
H
H
I
H
H
H
H
H
H
H
H
H
H
H
O
anti-29a
syn-29a
anti-29a
anti-29b
anti-29c
syn-29d
anti-29e
anti-29f
anti-30
91
71
90
Bu
Bu
Bu
Bu
Bu
35c
46c
98
syn-11e
anti-11g CO2Me BnO
anti-11j Ph i-Pr
CO2Me PhO
25c
64
anti-17a Ph
anti-11a Ph
S-Oxb Bu
S-Oxb Bu
96
anti-31a
anti-31b
anti-32
51c
45c
60
anti-11j
Ph
i-Pr
Bu
I
O
anti-29a Ph
S-Oxb
a
Yields are for pure products purified by column chromatog-
b
raphy. S-Ox ) (S)-4-phenyl-2-oxo-1,3-oxazolidin-3-yl. c Consid-
erable loss of material was observed in this case after chromato-
graphic purification.
In conclusion, an efficient, stereoselective entry to
fused bicyclic â-lactam systems from easily available
enyne-â-lactams has been developed. These compounds
are obtained if an activated double bond is present as
radical acceptor. In the absence of this condition, new
forms of reactivity were observed, including C3-C4 bond
cleavage of the â-lactam ring to yield tetrahydropyridine
derivatives and 1,5-radical translocation to yield new
bicyclic derivatives. Some simple transformations were
tested on representative examples of the different types
of bicyclic systems prepared to demonstrate their poten-
tial as intermediates in the preparation of other, differ-
ently functionalized systems. Efforts to develop this
methodology for the preparation of more elaborate car-
bapenems and carbacephems are currently underway in
our research group.
(()-tr a n s-3-Isop r op yl-1-p r op a r gyl-4-(E)-styr yl-2-a zeti-
d in on e (3c). Method B. From cinnamaldehyde (0.66 g, 5
mmol), propargylamine (0.27 g, 5 mmol), and isovaleryl
chloride (0.90 g, 10 mmol), 0.34 g of the title compound was
obtained. Flash chromatography (silica gel; hexanes/EtAcO,
5:1). Yield: 27%. Yellowish oil. 1H NMR (CDCl3) δ: 0.94 (d,
3H, J ) 6.6 Hz), 1.02 (d, 3H, J ) 6.6 Hz), 2.01 (m, 1H), 2.16
(t, 1H, J ) 2.7 Hz), 2.73 (dd, 1H, J ) 2.7, 8.4 Hz), 3.65 (dd,
1H, J ) 2.7, 18.0 Hz), 4.00 (dd, 1H, J ) 2.4, 8.7 Hz), 4.16 (dd,
(32) Sauer, J . C. Organic Syntheses; Collect. Vol. IV, p 813.
(33) Dumont, J . L.; Chodkiewicz, W.; Cadiot, P. Bull. Soc. Chim.
Fr. 1967, 2, 588.
(34) Schmid, C.; Bryant, J . D.; Dowlatzedah, M.; Phillips, J .; Prather,
D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J . Org. Chem. 1991,
56, 4056.
(35) Imwinnkelreid, R.; Hegedus, L. S. Organometallics 1988, 7, 702.
(36) (a) Pirkle, W. H.; Simmons, K. A. J . Org. Chem. 1983, 48, 2520.
(b) Evans, D. A.; Weber, A. E. J . Am. Chem. Soc. 1986, 108, 6761.
(37) Evans, D. A.; Sjo¨rgen, E. B. Tetrahedron Lett. 1985, 26, 3783.
(38) (a) Kliegman, J . M.; Barnes, R. K. J . Org. Chem. 1970, 35,
3140-3143. (b) Barnes, R. K.; Kliegman, J . M. Tetrahedron 1970, 26,
2555.
Exp er im en ta l Section
Gen er a l. General experimental data and procedures have
been previously reported.20 NMR spectra were recorded in
CDCl3 solutions, except as otherwise stated. Chemical shifts
are given in ppm relative to TMS (1H, 0.0 ppm) or CDCl3 (13C,
76.9 ppm). Specific rotation [R]D is given in degrees per dm at
20 °C, and the concentration (c) is expressed in grams per 100
mL in CHCl3. All commercially available compounds were used
without further purification. The following chemicals were
prepared according to literature procedures: propynal,32 4-bu-
(39) Full spectroscopic and analytical data for compounds not
included in this Experimental Section are described in the Supporting
Information.

5384 J . Org. Chem., Vol. 64, No. 15, 1999
Alcaide et al.
1
1H, J ) 2.7, 17.7 Hz), 6.10 (dd, 1H, J ) 8.4, 15.9 Hz), 6.62 (d,
1H, J ) 15.6 Hz), 7.2-7.4 (m, 5H). 13C NMR (CDCl3) δ: 169.1,
136.0, 134.1, 128.8, 128.3, 127.0, 126.7, 77.4, 72.2, 64.7, 58.0,
29.7, 28.2, 20.4, 20.2. IR (CHCl3) ν: 3300, 1750. EM (m/e): 254-
(M+ + 1, 25), 253(M+, 5), 211(84), 170(83), 129(77), 115(100),
91(45). Anal. Calcd for C17H19NO: C, 80.60; H, 7.56; N, 5.53.
Found: C, 80.82; H, 7.41; N, 5.20.
85-86 °C (EtAcO/hexanes). H NMR (CDCl3) δ: 2.31 (t, 1H,
J ) 2.4 Hz), 3.73 (s, 3H), 3.79 (dd, 1H, J ) 2.4, 17.7 Hz), 4.35
(dd, 1H, J ) 2.4, 17.7 Hz), 4.65 (dd, 1H, J ) 4.8, 8.4 Hz), 5.38
(d, 1H, J ) 4.8 Hz), 6.17 (dd, 1H, J ) 1.2, 15.9 Hz), 6.85-7.05
(m, 4H), 7.20-7.30 (m, 2H). 13C NMR (CDCl3) δ: 165.5, 164.4,
157.1, 140.1, 129.7, 127.2, 122.7, 115.7, 82.5, 75.7, 73.7, 58.6,
52.0, 30.2. IR (KBr) ν: 3240, 1760, 1715. Anal. Calcd for C16H15
-
(()-cis-1-Allyl-4-eth yn yl-3-p h en oxy-2-a zetid in on e (4a ).
Method B. From propynaldehyde (1.5 g, 27.8 mmol), allylamine
(1.9 g, 33.3 mmol), and phenoxyacetyl chloride (7.10 g, 42
mmol), 4.33 g of the title compound was obtained. Flash
chromatography (silica gel; hexanes/EtAcO, 2:1). Yield: 68%.
Yellow solid. Mp: 65-66 °C (hexanes/AcOEt). 1H NMR (CDCl3)
2.45 (d, 1H, J ) 2.1 Hz), 3.73 (dd, 1H, J ) 7.1, 15.5 Hz), 4.0-
4.20 (m, 1H), 4.58 (dd, 1H, J ) 2.1, 4.3 Hz), 5.2-5.3 (m, 3H),
5.2-5.9 (m, 1H), 6.9-7.0 (m, 3H), 7.2-7.4 (m, 2H). 13C NMR
(CDCl3) δ: 164.5, 157.3, 130.6, 129.7, 122.6, 119.7, 115.7, 81.2,
77.7, 77.3, 49.5, 43.3. IR (KBr) ν: 3290, 1750, 1590, 1490. Anal.
Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C,
73.86; H, 5.75; N, 6.20.
NO4: C, 67.36; H, 5.30; N, 4.91. Found: C, 67.24; H, 5.38; N,
4.89.
Gen er a l P r oced u r e for th e Syn th esis of 4-Vin yl-2-
a zetid in on es 2f,g. To a solution of the corresponding 4-[(S)-
1′,2′-dihydroxyethyl]-2-azetidinone 7 (4 mmol) in anhydrous
THF (100 mL) was added TCDI (4.84 mmol), and the mixture
was stirred until complete disappearance of the starting
product (TLC). The crude mixture was extracted with CH2Cl2
(4 × 10 mL) to give the corresponding thiocarbonate. A solution
of the aforementioned thiocarbonate (4 mmol) in trimethyl
phosphite (25 mL) was stirred at reflux until complete disap-
pearance of the starting material (TLC). Then, the solvent was
evaporated under vacuum, and the crude product was purified
by column chromatography to give the desired 4-vinyl-2-
azetidinone. A representative example for the preparation of
enyne-2-azetidinone 2f follows.
(+)-(3R,4S)-3-P h en oxy-1-p r op a r gyl-4-vin yl-2-a zet id i-
n on e (2f). From compound 7a (0.17 g, 0.64 mmol), 0.08 g of
the title compound was obtained. Flash chromatography (silica
gel, hexanes/EtAcO 6:1). Yield: 55%. Colorless oil. [R]D ) +10
(c ) 0.1, CHCl3). 1H NMR (CDCl3) δ: 2.26 (t, 1H, J ) 2.7 Hz),
3.73 (dd, 1H, J ) 2.7, 17.7 Hz), 4.33 (dd, 1H, J ) 2.7, 17.7
Hz), 4.50 (dd, 1H, J ) 4.5, 8.7 Hz), 5.29 (d, 1H, J ) 4.5 Hz),
5.35-5.51 (m, 2H), 5.81-5.93 (m, 1H), 6.9-7.3 (m, 5H). 13C
NMR (CDCl3) δ: 164.6, 157.2, 130.9, 129.6, 123.2, 122.3, 115.6,
81.8, 76.2, 73.0, 60.8, 29.6. IR (CHCl3) ν: 3290, 1760. Anal.
Calcd for C14H13NO2: C, 74.00; H, 5.77; N, 6.16. Found: C,
74.22; H, 5.99; N, 5.83.
Syn th esis of 4-Eth yn yl-1-(3′-m eth oxyca r bon yl-2′-p r o-
p en yl)-2-a zetid in on es 4d ,e. To a solution of the correspond-
ing 1-allyl-2-azetidinone 4a or 4b (1 mmol) and trimethylamine-
N-oxide (2 mmol) in acetone/water (80:10 mL) was added OsO4
in tert-butanol (2.5%, 0.1 mmol). The mixture was stirred at
room temperature for 2 h. Then, it was treated with an
aqueous solution of NaHSO3 (40%) for 30 min and extracted
several times with EtOAc. The organic layer was dried
(MgSO4), and the solvent was removed under vacuum to obtain
the corresponding diol, which was treated with NaIO4 (2 mmol)
and Ph3PdCHCO2Me (1.4 mmol) as stated for 2a . A repre-
sentative example for the preparation of enyne-2-azetidinone
4d follows.
(()-cis-4-Eth yn yl-1-(3′-m eth oxyca r bon yl-2′-p r op en yl)-
3-p h en oxy-2-a zetid in on e (4d ) From â-lactam 4a (0.71 g,
3.12 mmol), 0.51 g of a mixture of diastereoisomers, E/Z ratio
84:16, was obtained. Yield: 57%. An analytical sample of the
E-isomer was isolated by recristallization from the mixture.
Flash chromatography (silica gel, hexanes/EtAcO 4:1). E-
isom er . White solid. Mp: 95-96 °C (hexane/AcOEt). 1H NMR
(CDCl3) δ: 2.50 (d, 1H, J ) 2.1 Hz), 3.76 (s, 3H), 3.95 (ddd,
1H, J ) 1.4, 6.4, 17.0 Hz), 4.29 (ddd, 1H, J ) 1.8, 5.1, 17.0
Hz), 4.63 (dd, 1H, J ) 2.1, 4.3 Hz), 5.36 (d, 1H, J ) 4.3 Hz),
6.04 (dt, 1H, J ) 1.6, 15.6 Hz), 6.87 (ddd, 1H, J ) 5.2, 6.4,
15.6 Hz), 7.0-7.1 (m, 2H), 7.3-7.4 (m, 3H). 13C NMR (CDCl3)
δ: 166.0, 164.7, 157.2, 140.2, 129.7, 124.2, 122.7, 115.7, 81.6,
78.3, 75.4, 52.0, 50.1, 41.3. IR (KBr) ν: 3300, 1760, 1670. EM
(m/e): 286 (M - H+., 1), 144 (100), 116 (25), 115 (71), 105 (15),
77 (52), 65 (20), 51 (48). Anal. Calcd for C16H15NO4: C, 67.36;
H, 5.30; N, 4.91. Found: C, 67.54; H, 5.43; N, 4.69.
P r ep a r a tion of En yn e-2-a zetid in on es 2 a n d 4 by Wittig
Rea ction on Ald eh yd es 8-10. Representative examples for
the preparation of enyne-2-azetidinones by Wittig reaction
follow.
(+)-(3R,4S)-3-P h en oxy-1-p r op a r gyl-4-(E)-styr yl-2-a ze-
tid in on e (2a ). To a stirred solution of diol 7a (0.93 g, 3.55
mmol) in MeOH/H2O (5:1, 41 mL), NaIO4 (1.52 g, 7.12 mmol)
was added. After 30 min, the mixture was concentrated,
diluted with water, extracted with CH2Cl2 (×4), and dried
(MgSO4). After filtration and evaporation of the solvent, the
crude product was used as such in the next step. To a
suspension of benzyl triphenylphosphonium chloride (1.9 g,
4.97 mmol) in anhydrous THF (30 mL) under argon, BuLi (1.6
M in hexanes, 2.66 mL, 4.26 mmol) was added dropwise. The
red mixture was then stirred for 30 min at room temperature,
and a solution of the crude mixture of aldehyde 8 obtained
before in THF (20 mL) was then added. After 50 min, the
mixture was quenched with brine, extracted with EtAcO (×4),
and dried (MgSO4). After filtration and evaporation of the
solvent, the crude product was analyzed by 1H NMR, showing
a mixture of diastereoisomers, E/Z ratio 81:19. Purification was
performed by column chromatography (silica gel, hexanes/
EtAcO 4:1) and afforded 0.85 g of a mixture of isomers. Yield:
80%. An analytical sample of the E-isomer was isolated by
recrystallization from EtOH. E-Isom er . White crystals. [R]D
1
) - 23.5 (c ) 0.5, CHCl3). Mp: 110-111 °C (EtOH). H NMR
(CDCl3) δ: 2.27 (t, 1H, J ) 2.7 Hz), 3.78 (dd, 1H, J ) 2.7, 17.7
Hz), 4.33 (dd, 1H, J ) 2.4, 17.7 Hz), 4.67 (dd, 1H, J ) 4.5, 9.0
Hz), 5.37 (d, 1H, J ) 4.5 Hz), 6.21 (dd, 1H, J ) 9.0, 15.9 Hz),
6.76 (d, 1H, J ) 15.9 Hz), 6.95 (m, 3H), 7.20-7.30 (m, 7H).
13C NMR (CDCl3) δ: 164.5, 157.1, 137.3, 135.7, 129.4, 128.5,
128.3, 126.6, 122.2, 121.5, 115.4, 82.1, 76.1, 72.8, 60.4, 29.7.
IR (KBr) ν: 3250, 1755. Anal. Calcd for C20H17NO2: C, 79.18;
H, 5.65; N, 4.62. Found: C, 79.04; H, 5.55; N, 4.60.
(+)-(3R,4S)-4-(E or Z)-(2′-Meth oxyca r bon yl)eth en yl-3-
p h en oxy-1-p r op a r gyl-2-a zetid in on e (2c). Diol 7a (1.35 g,
5.17 mmol) was treated with NaIO4 as stated above for 2a .
The crude product obtained before was dissolved in anhydrous
THF (50 mL), Ph3PdCHCO2Me (2.07 g, 6.20 mmol) was added,
and the mixture was heated under reflux in an argon atmo-
sphere for 3 h. Then, the solvent was evaporated, and the crude
product (1H NMR analysis showed an E/Z ratio of 86:14) was
purified by column chromatography (silica gel, hexanes/EtAcO
3:1) to give, in sequence, 0.18 g (12%) of the Z-isomer as a
pale yellow oil and 1.20 g (82%) of the E-isomer as a white
solid. Yield: 94%. Z-Isom er . Pale yellow oil. [R]D ) +195 (c
Gen er a l P r oced u r e for th e Syn th esis of Bicycles 11-
13, 15, a n d 17. Meth od A. A solution of the corresponding
monocyclic 2-azetidinone (1 mmol), Bu3SnH or Ph3SnH (1.15
mmol), and AIBN (0.1 mmol) in anhydrous benzene (20 mL)
under argon was heated under reflux until complete disap-
pearance of starting material (TLC). Then, the solvent was
1
) 0.8, CHCl3). H NMR (CDCl3) δ: 2.28 (t, 1H, J ) 2.7 Hz),
3.74 (s, 3H), 4.01 (dd, 1H, J ) 2.7, 17.7 Hz), 4.19 (dd, 1H, J )
2.7, 17.7 Hz), 5.41 (d, 1H, J ) 4.8 Hz), 5.79 (ddd, 1H, J ) 1.5,
4.8, 9.0 Hz), 6.05 (dd, 1H, J ) 1.5, 11.7 Hz), 6.37 (dd, 1H, J )
9.0, 11.7 Hz), 6.95-7.05 (m, 3H), 7.20-7.30 (m, 2H). 13C NMR
(CDCl3) δ: 166.0, 164.9, 157.2, 142.0, 129.6, 125.6, 122.5, 115.6,
82.5, 76.3, 73.3, 56.1, 51.8, 30.5. Anal. Calcd for C16H15NO4:
C, 67.36; H, 5.30; N, 4.91. Found: C, 67.52; H, 5.61; N, 5.02.
E-Isom er . White crystals. [R]D ) +31 (c ) 1.2, CHCl3). Mp:
1
evaporated, and the crude product was analized by H NMR.
The residue was purified by column chromatography (silica
gel; hexanes, then hexanes/EtAcO or hexanes/Et3N mixtures).
Meth od B. A solution of Bu3SnH or Ph3SnH (1.15 mmol) and

Synthesis of Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 64, No. 15, 1999 5385
AIBN (0.1 mmol) in anhydrous benzene (10 mL) was added
using a syringe pump (at 2 mL/h rate) over a refluxing solution
of the corresponding â-lactam (1 mmol) in anhydrous benzene
(15 mL) under argon. Then, the solvent was evaporated, and
5.37 (dd, 1H, J ) 1.8, 4.2 Hz), 5.68 (dd with satellites, 1H, J
) 2.4, 4.5 Hz), 6.95-7.10 (m, 3H), 7.25-7.35 (m, 2H). 13C NMR
(CDCl3) δ: 171.7, 165.4, 157.3, 136.8, 135.5, 129.4, 122.1, 115.5,
81.5, 53.6, 51.6, 42.0, 37.5, 31.4, 28.9, 27.2, 13.6, 9.1. IR (CHCl3)
ν: 1750. Anal. Calcd for C28H43NO4Sn: C, 58.35; H, 7.52; N,
2.43. Found: C, 58.05; H, 7.77; N, 2.54.
1
the crude product was analyzed by H NMR. The residue was
purified by column chromatography (silica gel; hexanes, then
hexanes/EtAcO or hexanes/Et3N mixtures). In many cases, a
second chromatography was performed to isolate both isomers.
In these cases, the isolated yield is given for each isomer.
1-Ben zyl-2-(Z)-tr ibu tylstan n ylm eth ylen e-6-[(S)-4-ph en -
yl-2-oxo-1,3-oxa zolid in -3-yl]ca r ba p en a m s 11a . Method A
or B. From 0.37 g (1 mmol) of 1a , a 88:12 isomer mixture was
obtained. Flash chromatography (silica gel, hexanes/EtAcO
4:1) afforded in sequence the major isomer (0.53 g, 80%) and
the minor isomer (0.070 g, 11%). Total yield: 91%. Ma jor
(1R,5R,6S)-isom er 11a . Colorless oil. [R]D ) +187 (c ) 1,
1-Ben zyl-2-(Z)-tr ibu tylsta n n ylm eth ylen e-6-isop r op yl-
ca r ba p en a m s 11j. Method A or B. From 0.1 g (0.40 mmol) of
tr a n s-3c, a 90:10 mixture of two isomers was obtained. Flash
chromatography (silica gel, hexanes/AcOEt, 4:1) afforded 0.13
g of isomer mixture (60% yield). Ma jor (1S*,5S*,6S*)-isom er
11j. Colorless oil. Isolated yield: 50%. 1H NMR (CDCl3) δ: 0.42
(d, 3H, J ) 6.6 Hz), 0.6 (d, 3H, J ) 6.6 Hz), 0.8-1.4 (m, 27H),
1.6 (m, 1H), 2.28 (dd, 1H, J ) 1.5, 7.2 Hz), 2.36 (dd, 1H, J )
11.1, 13.8 Hz), 2.64 (br s, 1H), 3.04 (dd, 1H, J ) 1.5, 8.1 Hz),
3.23 (dd 1H, J ) 9.8, 13.8 Hz), 3.30 (dt, 1H, J ) 1.8, 3.3, 14.7
Hz), 4.16 (dc, 1H, J ) 1.2, 2.1, 3.6, 14.7 Hz), 5.86 (d with
satellites, 1H, J ) 2.1 Hz), 7.2 (m, 5H). 13C NMR (CDCl3) δ:
177.5, 162.0, 139.2, 128.7, 128.6, 126.4, 119.3, 64.8, 61.2, 51.5,
51.1, 37.0, 29.1, 27.9, 27.3, 19.9, 19.7, 13.7, 9.8. IR (CHCl3) ν:
1735, 1220. Anal. Calcd for C29H47NOSn: C, 63.98; H, 8.70;
N, 2.57. Found: C, 63.69; H, 8.89; N, 2.22.
6-Allyl-1-ben zyl-2-(Z)-tr ip h en ylsta n n ylm eth ylen eca r -
ba p en a m s 11l. Method A or B. From 0.80 g (0.32 mmol) of
tr a n s-3d , a 90:10 mixture of two isomers was obtained. Flash
chromatography (silica gel, hexanes/AcOEt, 5:1) afforded 0.18
g of the isomer mixture (92% yield). Ma jor (1S*,5S*,6S*)-
isom er 11l. Isolated yield: 52%. Colorless oil. 1H NMR
(CDCl3) δ: 1.96 (m, 2H), 2.35-2.50 (m, 2H), 2.7 (m, 1H), 3.05
(dd, 1H, J ) 1.5, 8.4 Hz), 3.23-3.32 (m, 2H), 4.0 (d, 1H, J )
15 Hz), 4.7-4.8 (m, 2H), 5.2 (m, 1H), 6.19 (d with satellites,
1H, J ) 2.1 Hz), 7.1-7.6 (m, 20H). 13C NMR (CDCl3) δ: 176.4,
165.8, 139.2, 137.7, 137.5, 137.4, 134.2, 129.6, 129.2, 129.0,
126.8, 117.2, 116.3, 62.0, 57.1, 52.6, 51.5, 36.8, 32.7. IR (CHCl3)
ν: 1750. EM (m/e): 603(M+ 120Sn, 2), 602(M+ 119Sn, 3), 600-
(M+117 Sn, 1), 526(9), 351(50), 197(63), 91(100). Anal. Calcd
for C35H33NOSn: C, 69.79; H, 5.52; N, 2.32. Found: C, 69.98;
H, 5.84; N, 2.10.
1
CHCl3). H NMR (CDCl3) δ: 0.7-1.6 (m, 27H), 2.28 (dd, 1H,
J ) 10.7, 13.0 Hz), 2.82 (dd, 1H, J ) 7.7, 8.9 Hz), 3.32 (dd,
1H, J ) 3.3, 13.4 Hz), 3.4-3.6 (m, 3H), 3.84 (t, 1H, J ) 8.1
Hz), 3.90 (d, 1H, J ) 3.9 Hz), 4.16 (t, 1H, J ) 8.9 Hz), 4.40 (d,
1H, J ) 13.4 Hz), 5.97 (d with satellites, 1H, J ) 2.1 Hz), 7.0-
7.6 (m, 10H). 13C NMR (CDCl3) δ: 171.8, 160.8, 157.3, 141.6,
137.0, 129.6, 129.4, 129.4, 129.1, 127.2, 126.5, 119.7, 70.9, 65.3,
59.4, 59.3, 52.4, 47.1, 37.9, 29.2, 27.4, 13.8, 10.0. IR (CHCl3)
ν: 1780, 1755. Anal. Calcd for C35H48N2O3Sn: C, 63.36; H,
7.29; N, 4.22. Found: C, 63.45; H, 7.35; N, 4.00. Min or
(1S,5R,6S)-isom er 11a . Colorless crystals. Mp: 94-95 °C
(hexanes/EtAcO). [R]D ) +49 (c ) 0.52, CHCl3). 1H NMR
(CDCl3) δ: 0.8-1.6 (m, 27H), 2.48 (dd, 1H, J ) 11.1, 14.3 Hz),
2.83 (m, 2H), 3.29 (br s, 1H), 3.39 (dd, 1H, J ) 4.3, 8.0 Hz),
3.48 (dd, 1H, J ) 2.0, 18.1 Hz), 4.01 (dd, 1H, J ) 6.2, 8.5 Hz),
4.1-4.3 (m, 2H), 4.33 (t, 1H, J ) 8.9 Hz), 5.62 (d with satellites,
1H, J ) 2.1 Hz), 7.1-7.5 (m, 10H). 13C NMR (CDCl3) δ: 162.7,
157.5, 140.3, 138.2, 136.7, 135.6, 129.6, 129.5, 129.2, 129.0,
127.4, 126.6, 70.9, 62.4, 58.9, 56.5, 42.4, 41.7, 36.4, 29.1, 27.5,
13.8, 9.3. IR (KBr) ν: 1760. Anal. Calcd for C35H48N2O3Sn: C,
63.36; H, 7.29; N, 4.22. Found: C, 63.39; H, 7.22; N, 4.19.
1-Be n zyl-2-(Z)-t r ip h e n ylst a n n ylm e t h yle n e -6-[(S )-4-
ph en yl-2-oxo-1,3-oxazolidin -3-yl]car bapen am s 11b. Method
A. From 0.15 g (0.40 mmol) of 1a , a 90:10 mixture of two
isomers was obtained. Flash chromatography (silica gel, hex-
anes/Et3N, 6:1) afforded the isomer mixture in 96% yield.
Ma jor (1R,5R,6S)-isom er 11b. Isolated yield: 72%. White
solid. Mp: 187-189 °C (hexanes/EtAcO). [R]D ) +189.1 (c )
1, CHCl3). 1H NMR (CDCl3) δ: 2.78 (dd, 1H, J ) 10.8, 13.8
Hz), 2.84 (dd, 1H, J ) 7.5, 8.7 Hz), 3.36-3.45 (m, 2H), 3.5-
3.65 (m, 2H), 3.83 (dd, 1H, J ) 8.7, 7.8 Hz), 3.85 (dd, 1H, J )
4.2, 0.9 Hz), 4.15 (t, 1H, J ) 8.7 Hz), 4.23 (d, 1H, J ) 14.1
Hz), 5.26 (d, 1H, J ) 2.1 Hz with satellites), 7.0-7.6 (m, 25H).
13C NMR (CDCl3) δ: 171.4, 165.0, 141.1, 141.1, 137.8, 137.6,
137.0, 136.9, 129.6, 129.4, 129.2, 128.9, 128.9, 127.2, 126.6,
116.2, 70.9, 65.2, 59.4, 59.4 52.5, 47.7, 37.9. IR (CHCl3) ν: 1750,
1780. Anal. Calcd for C41H36N2O3Sn: C, 68.07; H, 5.01; N, 3.87.
Found: C, 68.12; H, 5.04; N, 3.79.
1-Tr ibu tylstan n ylm eth ylen e-2-m eth oxycar bon ylm eth yl-
6-p h en oxyca r ba p en a m s 12b. Method A. From 0.2 g (0.70
mmol) of 4d , a 68:32 mixture of two isomers was obtained.
Flash chromatography (silica gel, hexanes/AcOEt, 5:1) afforded
0.29 g of isomer mixture (70% yield). Ma jor (2S*,5R*,6S*)-
isom er 12b. Isolated yield: 57%. White solid. Mp: 51-52 °C
1
(hexanes/AcOEt). H NMR (CDCl3) δ: 0.95 (m, 15H), 1.3 (m,
6H), 1.5 (m, 6H), 2.25 and 2.31 (ABX system, 2H, J ) 4.1, 9.2,
15.7 Hz), 2.79 (t, 1H, J ) 10.9 Hz), 3.15 (m, 1H), 3.68 (s, 3H),
4.2-4.4 (m, 2H), 5.45 (d, 1H, J ) 5.1 Hz), 6.16 (t, 1H, J ) 2.1
Hz), 7.0-7.1 (m, 3H), 7.3-7.4 (m, 2H). 13C NMR (CDCl3) δ:
177.7, 172.4, 157.4, 153.7, 129.5, 125.6, 122.4, 116.0, 82.8, 61.2,
53.3, 51.9, 45.3, 35.9, 29.3, 27.3, 13.7, 10.0. IR (KBr) ν: 1760,
1735. Anal. Calcd for C28H43NO4Sn: C, 58.35; H, 7.52; N, 2.43.
Found: C, 58.30; H, 7.34; N, 2.39.
4-Ben zyl-3-tr ibu tylstan n ylm eth ylen -6-p-m eth oxyph en -
yl-6-a za bicycle[3.2.0] h ep ta n -7-on e 13a . Method A. From
0.2 g (0.63 mmol) of 5a , a 78:22 mixture of two isomers was
obtained. Flash chromatography (silica gel, hexanes/AcOEt,
4:1) afforded 0.18 g (47% yield) of the isomer mixture. A further
purification allow us to isolate the major isomer for charac-
terization. Ma jor (1S*,4S*,5R*)-isom er 13a . Colorless oil. 1H
NMR (CDCl3) δ: 0.8-1.4 (m, 27H), 2.42-2.60 (m, 3H), 2.71
(dd, 1H, J ) 6.9, 13.5 Hz), 2.87 (dd, 1H, J ) 6.6, 9.6 Hz), 3.57
(dd, 1H, J ) 4.5, 7.5 Hz), 3.70 (s, 3H), 4.02 (d, 1H, J ) 3.9
Hz), 5.60 (s with satellites, 1H), 6.70 (d, 2H), 6.90 (d, 2H), 7.1-
7.3 (m, 5H) 13C NMR (CDCl3) δ: 165.7, 158.7, 155.9, 139.4,
131.1, 129.3, 128.6, 126.6, 126.6, 117.9, 114.4, 59.6, 55.6, 53.1,
51.4, 39.6, 32.7, 29.3, 27.4, 13.9, 10.1. IR (CHCl3) ν: 1745, 1620,
1510, 1380. EM (m/e): 552(M+ - Bu,100), 496(M+ - 2 × Bu,
2), 438(M+ - 3 × Bu, 81), 149(38). Anal. Calcd for C33H47NO2-
Sn: C, 65.14; H, 7.79; N, 2.30. Found: C, 65.26; H, 7.95; N,
2.09.
2-(Z)-Tr ibu t ylst a n n ylm et h ylen e-1-m et h oxyca r bon yl-
m eth yl-6-p h en oxyca r ba p en a m s 11e. Method A. From 0.78
g (2.74 mmol) of 2c (mixture of E/Z isomers), a 85:15 mixture
of two isomers was obtained. Flash chromatography (silica gel,
hexanes/EtAcO 4:1) afforded in sequence the major isomer
(0.91 g, 58%) and the minor isomer (0.19 g, 12%). Overall
yield: 80%. Ma jor (1S,5S,6R)-isom er 11e. Colorless oil. [R]D
) +10 (c ) 1.5, CHCl3). 1H NMR (CDCl3) δ: 0.8-1.6 (m, 27H),
2.42 (dd, 1H, J ) 7.2, 15.0 Hz), 2.60 (dd, 1H, J ) 5.1, 15.0
Hz), 3.1-3.2 (m, 1H), 3.51 (br d, 1H, J ) 15.3 Hz), 3.55 (s,
3H), 4.10 (dd, 1H, J ) 4.5, 8.4 Hz), 4.28 (br d, 1H, J ) 15.3
Hz), 5.48 (dd, 1H, J ) 1.2, 4.5 Hz), 5.81 (dd with satellites,
1H, J ) 2.7, 5.1 Hz), 6.95-7.05 (m, 3H), 7.25-7.35 (m, 2H).
13C NMR (CDCl3) δ: 174.6, 172.2, 159.5, 157.3, 129.7, 122.4,
120.5, 115.4, 79.7, 62.6, 51.8, 51.8, 41.2, 35.3, 29.2, 27.3, 13.8,
9.9. IR (CHCl3) ν: 1770, 1740, 1655. Anal. Calcd for C28H43
-
NO4Sn: C, 58.35; H, 7.52; N, 2.43. Found: C, 58.20; H, 7.25;
N, 2.33. Min or (1R,5S,6R)-isom er 11e: Colorless oil. [R]D
)
4-Ben zyl-6-p-m eth oxyp h en yl-3-tr ip h en ylsta n n ylm eth -
ylen -6-a za bicycle[3.2.0] h ep ta n -7-on e 13b. Method A. From
0.15 g (0.42 mmol) of 5a , a 88:12 mixture of two isomers was
obtained. Flash chromatography (silica gel, hexanes/AcOEt,
+61 (c ) 1, CHCl3). 1H NMR (CDCl3) δ: 0.8-1.6 (m, 27H),
2.32 (m, 2H), 3.1-3.2 (m, 1H), 3.52-3.63 (m, 1H), 3.59 (s, 3H),
3.73 (dd, 1H, J ) 4.2, 8.7 Hz), 4.18 (dt, 1H, J ) 3.0, 18.3 Hz),

5386 J . Org. Chem., Vol. 64, No. 15, 1999
Alcaide et al.
4:1) afforded 0.23 g (72% yield) of the isomer mixture. A further
purification allow us to isolate an analytical sample of the
major isomer. Ma jor (1S*,4S*,5R*)-isom er 13b. White solid.
8.4 Hz), 5.81 (s, 1H), 6.66 (dd, 1H, J ) 2.1, 8.1 Hz), 6.9-7.3
(m, 5H). 13C NMR (CDCl3) δ: 164.5, 151.0, 137.5, 129.5, 125.1,
122.1, 123.0, 121.6, 114.7, 67.2, 54.3, 47.0, 29.1, 27.2, 21.5, 13.7,
10.2. IR (CHCl3) ν: 1740. Anal. Calcd for C27H43NO2Sn: C,
60.92; H, 8.14; N, 2.63. Found: C, 61.11; H, 8.36; N, 2.81.
Gen er a l P r oced u r e for th e Syn th esis of Ca r ba p en a m s
20 a n d 21a . A solution of the â-lactam 1a (1 mmol), the
corresponding radical promoter (Ph2PH or BrTs, 1.15 mmol),
and AIBN (0.1 mmol) in anhydrous benzene (20 mL) under
argon was heated under reflux with the addition of AIBN every
2 h until complete disappearance of starting material (TLC,
7-8 h). Then, the solvent was evaporated, and the crude
product was analized by 1H NMR. The residue was purified
by column chromatography (silica gel; hexanes, then hexanes/
EtAcO).
1
Mp: 172-174 °C (hexane/AcOEt). H NMR (CDCl3) δ: 2.39-
2.61(m, 2H), 2.69 (dd, 1H, J ) 9.9, 13.5 Hz), 2.82 (dd, 1H, J )
6.6, 13.5 Hz), 3.11 (dd, 1H, J ) 7.2, 9.6 Hz), 3.55 (dd, 1H, J )
3.9, 8.7 Hz), 3.75 (s, 3H), 4.12 (d, 1H, J ) 4.2 Hz), 5.96 (d with
satellites, 1H, J ) 2.1 Hz), 6.8 (d, 2H), 7.1 (d, 2H), 7.2-7.4
(m, 20H). 13C NMR (CDCl3) δ: 165.0, 162.6, 155.8, 138.8, 138.2,
136.8, 130.8, 129.1, 128.9, 128.9, 128.5, 126.6, 122.3, 117.7,
114.3, 59.4, 55.4, 53.0, 51.7, 39.4, 33.1. IR (CHCl3) ν: 1740,
1510, 1480, 1430. EM (m/e): 665.10(M+ 116Sn), 667.05(M+
118Sn), 668.10(M+ 119Sn), 669.10(M+ 120Sn). Anal. Calcd for
C
39H35NO2Sn: C, 70.08; H, 5.28; N, 2.10. Found: C, 70.24; H,
5.34; N, 2.41.
[1R*,3S*,4R*,5R*]-6-Allyl-4-tr ibu tylesta n n ylm eth yl-3-
ph en yl-2-oxa-6-azabicycle[3.2.0]h eptan -7-on e (15a). Method
A. From 0.12 g (0.50 mmol) of 4b, only one diastereomer was
obtained. Flash chromatography (silica gel, hexanes/AcOEt,
5:1) afforded 0.2 g of the title compound. Yield: 85%. Yellow
Com p ou n d s 20a a n d 20b. From 0.3 g of 1a , only one
diastereoisomer of compound 20a was obtained but could not
be isolated as such because of oxidation to 20b during
chromatographic purification. (1R,5R,6S)-Dip h en ylp h os-
1
p h in e d er iva tive 20a (from the crude reaction mixture). H
1
oil. H NMR (CDCl3) δ: 0.25 (m, 2H), 0.90 (m, 15H), 1.3 (m,
NMR (CDCl3) δ: 2.41 (dd, 1H, J ) 10.8, 12.9 Hz), 2.90 (dd,
1H, J ) 7.8, 9.0 Hz), 3.36 (dd, 1H, J ) 3.9, 12.9 Hz), 3.60 (m,
2H), 3.87 (dd, 1H, J ) 7.8, 9.0 Hz), 3.92 (d, 1H, J ) 3.9 Hz),
4.01 (d, 1H, J ) 16.2 Hz), 4.19 (t, 1H, J ) 9.0 Hz), 4.38 (dd,
1H, J ) 1.5, 16.2 Hz), 6.24 (d, 1H, J ) 1.5 Hz), 7-7.5 (m, 20H).
(1R,5R,6S)-Dip h en ylp h osp h in e oxid e d er iva tive 20b. A
0.34 g portion of the phosphine oxide derivative was obtained.
Yield: 74%. Yellowish solid. Mp: >230 °C (dec). [R]D ) +100
(c ) 2, CHCl3).1H NMR (CDCl3) δ: 2.48 (dd, 1H, J ) 11.4,
13.2 Hz), 2.97 (dd, 1H, J ) 7.5, 9.0 Hz), 3.27 (dd, 1H, J ) 4.2,
13.2 Hz), 3.61 (dd, 1H, J ) 4.2, 8.4 Hz), 3.75 (m, 1H), 3.88
(dd, 1H, J ) 7.5, 9.0 Hz), 3.93 (d, 1H, J ) 4.2 Hz), 4.21 (t, 1H,
J ) 9.0 Hz), 4.25 (d, 1H, J ) 17.7 Hz), 4.5 (d, 1H, J ) 17.7
6H), 1.40 (m, 6H), 2.5 (dt, 1H, J ) 4.8, 11.1 Hz), 3.83 (m, 2H),
4.05 (dd, 1H, J ) 5.8, 15.6 Hz), 5.2-5.3 (m, 4H), 5.83 (m, 1H,
J ) 2.2 Hz), 7.2-7.4 (m, 5H). 13C NMR (CDCl3) δ: 166.1, 137.3,
132.1, 128.2, 127.3, 126.3, 119.0, 86.0, 83.5, 65.7, 43.3, 41.7,
29.3, 27.4, 13.8, 9.2, 5.2. IR (CHCl3) ν: 1710, 1645, 1605. Anal.
Calcd for C27H43NO2Sn: C, 60.96; H, 8.14; N, 2.63. Found: C,
60.82; H, 8.16; N, 2.59.
[1R*,3S*,4R*,5R*]-6-(p-An isyl)-4-tr ibu tylstan n ylm eth yl-
3-p h en yl-2-oxa -6-a za b icycle[3.2.0]h ep t a n -7-on e (15d ).
Method A. From 0.2 g (0.65 mmol) of 16b, a 62:38 mixture of
cyclyzation product/reduction was obtained. Flash chromatog-
raphy (silica gel, hexanes/AcOEt, 7:1) afforded 0.24 g of the
title compound. Yield: 62%. White solid. Mp: 116-117 °C
(hexane/AcOEt). 1H NMR (CDCl3) δ: 0.35 (m, 2H), 0.8-1.4
(m, 27H), 2.71 (dt, 1H, J ) 4.5, 11 Hz), 3.8 (s, 3H), 4.22 (d,
1H, J ) 3.6 Hz), 5.16 (d, 1H, J ) 4.3 Hz), 5.30 (d, 1H, J ) 3.6
Hz), 6.90-7.4 (m, 4H), 7.2-7.3 (m, 5H). 13C NMR (CDCl3) δ:
163.1, 156.7, 137.1, 130.4, 128.2, 127.4, 126.3, 118.6, 114.7,
84.9, 83.6, 65.3, 55.7, 41.5, 29.2, 27.5, 13.8, 9.5, 5.4. IR (KBr)
ν: 2960, 2900, 1730, 1510. Anal. Calcd for C31H45NO3Sn: C,
62.22; H, 7.58; N, 2.34. Found: C, 62.16; H, 7.28; N, 2.27.
(+)-(1R,6R,7S)-1-Ben zyl-2-(Z)-tr ibu tylstan n ylm eth ylen e-
7-[(S)-4-ph en yl-2-oxo-1,3-oxazolidin -3-yl]car bacefam (17a).
Method A. From 0.25 g (0.65 mmol) of 1b, only one isomer
was obtained. Flash chromatography (silica gel, hexanes/Et3N,
6:1) afforded 0.3 g of the title compound. Yield: 70%. Colorless
Hz), 6.18 (dd, 1H, J ) 2.7, J P-H ) 20 Hz), 7-7.5 (m, 20H). 13
C
NMR (CDCl3) δ: 170.8, 168.3, 157.4, 139.8, 136.7, 132.7, 131.1
(5 peaks), 129.2 (13 peaks), 127.1, 126.8, 70.8, 64.6, 63.8, 59.4,
59.1, 49.5, 37.6. IR (KBr) ν: 1780, 1750, 1420. Anal. Calcd for
C
35H31N2PO4: C, 73.16; H, 5.44; N, 4.88. Found: C, 73.48; H,
5.13; N, 4.54.
1-(r-Br om oben zyl)-2-(Z-p-tolu en esu lfon ylm eth ylen e)-
6-[(S)-4-ph en yl-2-oxo-1,3-oxazolidin -3-yl]car bapen am s 21a.
From 0.30 g of 1a , a 90:10 mixture of two isomers was
obtained. Ma jor isom er . A 0.34 g portion of the title com-
pound was isolated. Yield: 85%. White solid. Mp: >120 °C
(dec). [R]D ) +184 (c ) 1, CHCl3). 1H NMR (CDCl3) δ: 2.44 (s,
3H), 4.03 (m, 3H), 4.12-4.22 (m, 2H), 4.32 (d, 1H, J ) 4.5 Hz),
4.38 (t, 1H, J ) 8.1 Hz), 4.95 (dd, 1H, J ) 2.4, 18.6 Hz), 5.14
(d, 1H, J ) 5.7 Hz), 5.87 (d, 1H, J ) 2.4 Hz), 7.2-7.4 (m, 12H),
7.7 (d, 2H J ) 9.0 Hz). 13C NMR (CDCl3) δ: 170.7, 158.3, 144.8,
139.0, 137.6, 136.7, 135.5, 130.0, 129.7, 129.6, 129.3, 129.0,
127.9, 127.3, 127.1, 125.4, 70.9, 61.8, 60.5, 60.1, 55.0, 51.8, 49.4,
21.7. IR (KBr) ν: 1780, 1740. Anal. Calcd for C30H27N2O5SBr:
C, 59.31; H, 4.48; N, 4.61. Found: C, 59.60; H, 4.34; N, 4.89.
(1R,5R,6S)-1-(Ben zyl)-2-(Z-p-tolu en esu lfon ylm eth ylen e)-
6-[(S)-4-ph en yl-2-oxo-1,3-oxazolidin -3-yl]car bapen am s 21b.
To a refluxing solution of 0.08 g (0.13 mmol) of 21a and AIBN
(1 mg) in benzene (3 mL) under argon was added HSnBu3 (0.02
mL). Analysis of the crude mixture by 1H NMR showed
completed transformation. Purification was performed by
column chromatography to give 0.04 g of the title compound.
Yield: 62%. Colorless oil. [R]D ) +102.8 (c ) 3, CHCl3). 1H
NMR (CDCl3) δ: 2.45 (s, 3H), 2.96 (t, 1H, J ) 7.8 Hz), 3.12
(dd, 1H, J ) 3.6, 13.2 Hz), 3.70 (m, 3H), 3.88 (t, 1H, J ) 7.5
Hz), 3.94 (d, 1H, J ) 3.9 Hz), 4.20 (t, 1H, J ) 9.0 Hz), 4.37 (d,
1H, J ) 18.3 Hz), 4.76 (dd, 1H, J ) 2.4, 18.3 Hz), 6.30 (d, 1H,
J ) 2.4 Hz), 7.0 (m, 2H), 7.1-7.4 (m, 10H), 7.8 (m, 2H). 13C
NMR (CDCl3) δ: 170.6, 161.9, 157.4, 144.9, 139.1, 137.8, 136.5,
135.4, 130.1, 129.5, 129.4, 129.1, 127.5, 127.0, 123.8, 111.3,
70.8, 63.7, 59.4, 59.1, 48.8, 46.9, 37.3, 21.6. IR (KBr) ν: 1760,
1740. Anal. Calcd for C30H28N2O5S: C, 70.02; H, 5.48; N, 2.72.
Found: C, 70.20; H, 5.31; N, 2.99.
1
oil. [R]D ) +21.1 (c ) 1, CHCl3). H NMR (CDCl3) δ: (50 °C)
0.8-1.4 (m, 27H), 1.63 (m, 1H), 2.05 (m, 1H), 2.16 (br s, 1H),
2.63 (dd, 1H, J ) 6.0, 14.1 Hz), 2.63 (m, 1H), 2.82 (br s, 1H),
3.05 (dd, 1H, J ) 6.6, 14.7 Hz), 3.31 (dd, 1H, J ) 4.5, 10.2
Hz), 3.94 (m, 1H), 4.03 (dd, 1H, J ) 6.0, 7.8 Hz), 4.25 (br s,
1H), 4.38 (t, 1H, J ) 9.0 Hz), 5.77 (s with satellites, 1H), 7.2-
7.4 (m, 10H). 13C NMR δ: 163.0, 157.8, 153.6, 140.4, 138.3,
129.3, 129.2, 129.0, 128.6, 127.8, 126.1, 123.9, 77.2, 70.9, 63.2,
62.0, 59.1, 44.3, 41.7, 37.4, 29.3, 27.2, 13.5, 10.5. IR (CHCl3)
ν: 1750, 1720, 1220. EM (m/e): 621(M+ 120Sn - Bu, 60), 622-
(M+ 121Sn - Bu, 20), 620(M+ 120Sn - Bu, 31), 619(M+ 120Sn -
Bu, 46), 91(100), 57(18). Anal. Calcd for C36H50N2O3Sn: C,
63.82; H, 7.44; N, 4.13. Found: C, 63.95; H, 7.26; N, 4.02.
Tetr a h yd r op yr id in e 14a . From 0.31 g of 3a and Bu3SnH,
0.06 g (10%) of tetrahydropyridine 14a were obtained as a
colorless oil. 1H NMR (CDCl3) δ: 0.8-1.4 (m, 27H), 1.64 (s,
3H), 3.73 (d, 1H, J ) 14.5 Hz), 3.92 (s, 1H), 4.30 (s, 2H), 4.39
(d, 1H, J ) 14.5 Hz), 4.64 (s, 2H), 5.95 (s, 1H), 6.67 (s, 1H),
7.2-7.4 (m, 10H). 13C NMR (CDCl3) δ: 165.8, 150.2, 142.0,
137.4, 128.5, 128.5, 128.4, 128.2, 128.2, 128.1, 127.9, 127.6,
121.2, 117.6, 73.1, 69.2, 56.3, 45.2, 29.2, 19.7, 13.8, 10.4. IR
(CHCl3) ν: 1740. Anal. Calcd for C34H49NO2Sn: C, 65.61; H,
7.93; N, 2.25. Found: C, 65.42; H, 7.82; N, 2.55.
Tetr a h yd r op yr id in e 14b. From 0.2 g of 2e and Bu3SnH,
0.2 g (45%) of hydrostannylation product and 0.06 g (14%) of
14b were obtained. 1H NMR (CDCl3) δ: 0.8-1.4 (m, 27H), 1.18
(d, 3H, J ) 7.2 Hz), 3.0 (m, 1H), 4.08 (d, 1H, J ) 14.1 Hz),
4.32 (d, 1H, J ) 14.1 Hz), 4.74 (s, 2H), 4.97 (dd, 1H, J ) 2.1,
Gen er a l P r oced u r e for th e P r ep a r a tion of Ca r ba p -
en a m Der iva tives 29 a n d 30. A mixture of the corresponding
tin derivative 11, 17, p-TsOH‚H2O (1.2 equiv), and CH2Cl2 (30
mL/mmol) was stirred at room temperature until complete

Synthesis of Fused Bicyclic â-Lactams
J . Org. Chem., Vol. 64, No. 15, 1999 5387
disappearance of the starting material (TLC, 15-35 min).
After dilution with CH2Cl2, the mixture was successively
washed with 5% NaHCO3 and H2O and dried (MgSO4). After
filtration and evaporation of the solvent, the crude product
was purified by column chromatography (silica gel; hexanes/
EtAcO or hexanes/Et3N mixtures) and/or recrystallization.
Representative examples follow.
(+)-(1R,5R,6S)-1-Ben zyl-2-m eth ylen e-6-[(S)-4-p h en yl-2-
oxo-1,3-oxazolidin -3-yl]-car bapen am (a n ti-29a). From 0.31
g of m a jor 11a , 0.16 g of the title compound was obtained.
Yield: 91%. White needles. Mp: >197 °C (dec) (hexanes/
EtAcO). [R]D ) +229 (c ) 0.5, CHCl3). 1H NMR (CDCl3) δ: 2.36
(dd, 1H, J ) 11.0, 13.2 Hz), 2.86 (dd, 1H, J ) 7.6, 9.0 Hz),
3.33 (dd, 1H, J ) 3.6, 13.2 Hz), 3.4-3.6 (m, 1H), 3.55 (d, 1H,
J ) 4.3 Hz), 3.63 (d, 1H, J ) 14.9 Hz), 3.85 (dd, 1H, J ) 7.7,
8.5 Hz), 3.90 (d, 1H, J ) 4.7 Hz), 4.18 (t, 1H, J ) 8.9 Hz), 4.44
(d, 1H, J ) 14.9 Hz), 5.13 (d, 2H, J ) 2.1 Hz), 7.0-7.6 (m,
10H). 13C NMR (CDCl3) δ: 171.9, 157.8, 152.9, 141.1, 137.0,
129.6, 129.4, 129.3, 129.2, 127.2, 126.6, 107.4, 70.9, 65.2, 59.4,
59.1, 50.9, 44.9, 37.5. IR (KBr) ν: 1770, 1750, 1650. Anal. Calcd
for C23H22N2O3: C, 73.78; H, 5.92; N, 7.48. Found: C, 73.73;
H, 6.00; N, 7.48.
(+)-(1S,5R,6S)-1-Ben zyl-2-m eth ylen e-6-[(S)-4-p h en yl-2-
oxo-1,3-oxa zolid in -3-yl]-ca r ba p en a m (syn -29a ). From 0.10
g of syn -11a , 0.04 g of the title compound was obtained.
Yield: 71%. White crystals. Mp: 198-199 °C (hexanes/EtAcO).
[R]D ) + 43 (c ) 0.5, CHCl3). 1H NMR (CDCl3) δ: 2.46 (dd,
1H, J ) 11.3, 14.3 Hz), 2.82 (br d, 2H, J ) 9.9 Hz), 3.40 (br s,
1H), 3.3-3.5 (m, 2H), 3.9-4.1 (m, 3H), 4.30 (t, 1H, J ) 9.0
Hz), 5.6-5.7 (m, 2H), 7.1-7.5 (m, 10H). 13C NMR (CDCl3) δ:
163.2, 157.5, 140.1, 138.1, 138.1, 129.5, 129.2, 129.0, 128.8,
127.3, 126.7, 122.2, 71.0, 62.2, 59.0, 56.8, 41.4, 37.5, 34.7. IR
(KBr) ν: 1750. Anal. Calcd for C23H22N2O3: C, 73.78; H, 5.92;
N, 7.48. Found: C, 73.41; H, 6.03; N, 7.28.
washed with 10% NaHSO3 and H2O and dried (MgSO4). After
filtration and evaporation of the solvent, the crude product
was purified by column chromatography (silica gel, hexanes/
Et3N, 6:1). A 0.06 g (51%) portion of 31a could be obtained by
crystallization of one of the purer fractions. White crystals.
Mp: >121 (dec, hexane/EtAcO). [R]D ) +234 (c ) 0.5, CHCl3).
1H NMR (CDCl3) δ: 2.43 (dd, 1H, J ) 11.1, 13.2 Hz), 2.92 (dd,
1H, J ) 7.5, 9.0 Hz), 3.24 (dd, 1H, J ) 3.9, 13.2 Hz), 3.5-3.6
(m, 1H,), 3.62 (br d, 1H, J ) 15.9 Hz), 3.69 (dd, 1H, J ) 4.5,
8.4 Hz), 3.87 (dd, 1H, J ) 7.5, 8.4 Hz), 3.93 (dd, 1H, J ) 0.9,
4.2 Hz), 4.19 (t, 1H, J ) 9.0 Hz), 4.36 (br d, 1H, J ) 15.9 Hz),
6.23 (dd, 1H, J ) 2.4, 5.4 Hz), 7.0-7.5 (m, 10H). 13C NMR δ:
171.1, 157.4, 155.7, 140.1, 136.8, 129.6, 129.5, 129.3, 129.3,
127.2, 126.9, 71.1, 70.9, 66.2, 60.0, 59.5, 55.7, 47.7, 37.7. IR
(CHCl3) ν: 1760. Anal. Calcd for C23H21N2O3I: C, 55.21; H,
4.23; N, 5.60. Found: C, 54.91; H, 4.26; N, 5.40.
(+)-(1R,5R,6S)-1-Ben cyl-2-oxo-6-[(S)-4-p h en yl-2-oxo-
1,3-oxa zolid in -3-yl]-ca r b a p en a m (a n ti-32). Ozone was
passed through a solution of a n ti-29a (0.07 g, 0.19 mmol) in
CH2Cl2 (10 mL) at -78 °C until blue color was persistent (2
min). Excess Me2S (1 mL) was then added, and the mixture
was stirred overnight at room temperature. Then, it was
diluted, washed with water, dried (MgSO4), and evaporated.
Crude product was purified by column chromatography (silica
gel, EtAcO/hexanes 1:1) to give 0.04 g of the 2-oxocarbapenam
32. Yield: 60%. White needles. Mp: 194-196 °C (hexanes/
EtAcO). [R]D ) +236 (c ) 0.5, CHCl3). 1H NMR (CDCl3) δ: 2.35
(dd, 1H, J ) 11.4, 13.8 Hz), 3.03 (t, 1H, J ) 8.4 Hz), 3.28 (dd,
1H, J ) 0.9, 18.0 Hz), 3.28-3.38 (m, 1H), 3.42 (dd, 1H, J )
3.6, 13.5 Hz), 3.77 (dd, 1H, J ) 4.8, 9.0 Hz), 3.90 (dd, 1H, J )
7.8, 8.4 Hz), 4.13 (dd, 1H, J ) 0.9, 4.8 Hz), 4.19 (t, 1H, J ) 8.9
Hz), 4.23 (d, 1H, J ) 17.7 Hz), 7.0-7.5 (m, 10H). 13C NMR
(CDCl3) δ: 212.0, 170.2, 157.6, 139.9, 136.2, 129.6, 129.6, 129.3,
128.9, 127.1, 126.8, 71.0, 62.2, 61.2, 59.4, 51.7, 50.6, 34.3. IR
(KBr) ν: 1785, 1740. Anal. Calcd for C22H20N2O4: C, 70.20;
H, 5.35; N, 7.44. Found: C, 70.35; H, 5.62; N, 7.12.
(+)-(1R,5S,6R)-1-Meth oxycar bon ylm eth yl-2-m eth ylen e-
6-p h en oxyca r ba p en a m (syn -29d ). From 0.10 g of syn -11e,
0.05 g of the title compound was obtained. Yield: 98%.
1
Colorless oil. [R]D ) +189.4 (c ) 1, CHCl3). H NMR (CDCl3)
Ack n ow led gm en t. Support for this work by the
D.G.E.S.-M.E.C. (Project PB96-0565) is gratefully ac-
knowledged. A. Rodr´ıguez-Vicente acknowledges the
receipt of a predoctoral fellowship by the M.E.C. (Spain).
δ: 2.36 (m, 2H), 3.05-3.18 (m, 1H), 3.50 (br d, 1H), 3.60 (s,
3H), 3.73 (dd, 1H, J ) 4.2, 8.7 Hz), 4.12 (dd, 1H, J ) 3.6, 18.3
Hz), 5.39 (dd, 1H, J ) 1.8, 4.2 Hz), 5.7 (s, 2H), 6.95-7.35 (m,
5H). 13C NMR δ: 171.8, 166.1, 157.5, 129.7, 128.1, 122.8, 122.4,
115.7, 81.5, 54.0, 51.9, 37.4, 37.1, 29.9. IR (KBr) ν: 1760. Anal.
Calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.87. Found: C,
66.99; H, 5.88; N, 5.02.
Su p p or tin g In for m a tion Ava ila ble: Compound charac-
terization data and experimental procedures for products 1b,c,
2b, 2d ,e, 2g, 3a ,b, 3d , 4b,c, 4e, 5a ,b, 6a ,b, 7a ,b, 10, 11c,d ,
11f-i, 11k , 12a , 12c, 13c,d , 15b,c, 16a ,b, 17b, 19, a n ti-29b,c,
a n ti-29e,f, a n ti-30, a n ti-31, and 33, as well as X-ray data
for compound a n ti-29a . This material is available free of
charge via the Internet at http: //pubs.acs.org.
(+)-(1R,5R,6S)-1-Ben zyl-2-(Z)-iod om eth ylen e-6-[(S)-4-
p h en yl-2-oxo-1,3-oxa zolid in -3-yl]-ca r ba p en a m (a n ti-31a ).
To a solution of 0.15 g (0.23 mmol) of a n ti-11a in CH2Cl2 (10
mL) was added 63 mg (0.25 mmol) of iodine. The mixture was
stirred at room temperature until complete disappearance of
starting material (TLC). Then, the mixture was successively
J O9823994