Alkyne-Co2(CO)6 complexes in the synthesis of fused tricyclic β- lactam and azetidine systems

Article abstract of DOI:10.1021/jo980114h

A synthetic approach to racemic and enantiomerically pure, fused tricyclic 2-azetidinones and azetidines has been developed by using a Pauson- Khand (P-K) reaction on monocyclic enyne-β-lactams as the key synthetic step. The access to cyclization precursors, monocyclic β-lactams 1-7, was achieved by Staudinger reaction of enyne imines 8 and 9 and D-glyceraldehyde imines 10 and (benzyloxy)- or phenoxyacetyl chlorides. Enyne imines 8 and 9 formed cis-2-azetidinones 1 and 2 having the required enyne moiety. cis-2- Azetidinones 11 were obtained as single diastereomers and transformed to enyne-2-azetidinones 3 and 5 by standard methodology. Alternatively, 4- formyl-2-azetidinones 14 were prepared by cyclization of p-anisyl glyoxal diimine and (benzyloxy)acetyl chloride and converted to racemic enyne-β- lactams 4 and 6 by standard reactions. Enyne-2-azetidinones 1-7 were reacted with Co₂(Co)₈ to quantitatively yield the corresponding alkyne-Co₂(CO)₆ complexes. Reaction of such complexes with different promoters, especially heat and TMANO, formed tricyclic 2-azetidinones 15-19 with the ring system fused to the C3-C4 and C4-N1 lactam bonds. Yields were usually high, and the processes were highly diastereoselective. The exceptions were enyne-2- azetidinones 2 and 3a bearing N-propargyl moieties. These products decomposed to mixtures of unidentifiable products. Inhibition of the amide resonance was postulated as responsible for the failure of β-lactams 2 and 3a to form tricyclic systems. In fact, the analogous enyne-azetidines 20a,b smoothly cyclized to form the corresponding tricyclic systems. This approach to tricyclic azetidines was extended to prepare different products. A new, unprecedented, N1-C2 bond breakage was also observed in the azetidine ring. The results described show that the P-K reaction is a suitable approach to tricyclic 2-azetidinones and azetidines. These are the first examples reported for a P-K reaction in with the enyne system is tethered to a strained heterocyclic four-membered ring.

Full text of DOI:10.1021/jo980114h

6786
J . Org. Chem. 1998, 63, 6786-6796
Articles
Alk yn e-Co2(CO)6 Com p lexes in th e Syn th esis of F u sed Tr icyclic
â-La cta m a n d Azetid in e System s†,1
Benito Alcaide,* Concepcio´n Polanco, and Miguel A. Sierra
Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad Complutense,
28040-Madrid, Spain
Received J anuary 22, 1998
A synthetic approach to racemic and enantiomerically pure, fused tricyclic 2-azetidinones and
azetidines has been developed by using a Pauson-Khand (P-K) reaction on monocyclic enyne-
â-lactams as the key synthetic step. The access to cyclization precursors, monocyclic â-lactams
1-7, was achieved by Stau¨dinger reaction of enyne imines 8 and 9 and D-glyceraldehyde imines
10 and (benzyloxy)- or phenoxyacetyl chlorides. Enyne imines 8 and 9 formed cis-2-azetidinones
1 and 2 having the required enyne moiety. cis-2-Azetidinones 11 were obtained as single
diastereomers and transformed to enyne-2-azetidinones 3 and 5 by standard methodology.
Alternatively, 4-formyl-2-azetidinones 14 were prepared by cyclization of p-anisyl glyoxal diimine
and (benzyloxy)acetyl chloride and converted to racemic enyne-â-lactams 4 and 6 by standard
reactions. Enyne-2-azetidinones 1-7 were reacted with Co2(CO)8 to quantitatively yield the
corresponding alkyne-Co2(CO)6 complexes. Reaction of such complexes with different promoters,
especially heat and TMANO, formed tricyclic 2-azetidinones 15-19 with the ring system fused to
the C3-C4 and C4-N1 lactam bonds. Yields were usually high, and the processes were highly
diastereoselective. The exceptions were enyne-2-azetidinones 2 and 3a bearing N-propargyl
moieties. These products decomposed to mixtures of unidentifiable products. Inhibition of the
amide resonance was postulated as responsible for the failure of â-lactams 2 and 3a to form tricyclic
systems. In fact, the analogous enyne-azetidines 20a ,b smoothly cyclized to form the corresponding
tricyclic systems. This approach to tricyclic azetidines was extended to prepare different products.
A new, unprecedented, N1-C2 bond breakage was also observed in the azetidine ring. The results
described show that the P-K reaction is a suitable approach to tricyclic 2-azetidinones and
azetidines. These are the first examples reported for a P-K reaction in with the enyne system is
tethered to a strained heterocyclic four-membered ring.
In tr od u ction
common feature. Starting from the trinem nucleus
(formerly known as tribactam and, in terms of antibiotic
activity, still an unsurpassed reference),6 different poly-
cyclic 2-azetidinone systems have been recently reported.7
Most of the approaches to these compounds rest in the
stepwise preparation of a functionalized 2-azetidinone,
followed by the central ring closure by methods that have
been used for many years in the preparation of bicyclic
â-lactams.8 A dramatically different and impressive
approach to trinem-related tricyclic structures has been
recently disclosed.9 In this route, an in situ generated
azometine ylide reacted with a six-membered dipolaro-
Recent trends in â-lactam chemistry focus on the
preparation of structures far away from the classical
penem, cefem, and even carbapenem series.2 The in-
creased resistance of bacteria to the commonly used
â-lactam antibiotics3 and the evergrowing new applica-
tions of these products in fields ranging from enzyme
inhibition4 to the use of 2-azetidinones as starting
materials to develop new synthetic methodologies5 has
triggered a renewed interest in the building of new
polycyclic systems having the 2-azetidinone ring as
† This work is respectfully dedicated to the memory of J uan
Francisco de Andre´s, a teacher.
(6) (a) Tamburini, B.; Perboni, A.; Rossi, T.; Donati, D.; Andreotti,
D.; Gaviraghi, G.; Carlesso, R.; Bismara, C. Eur. Pat. Appl. EP0416953
A2, 1991; Chem. Abstr. 1992, 116, 235337t. (b) Perboni, A.; Rossi, T.;
Gaviraghi, G.; Ursini, A.; Tarzia, G. WO 9203437, 1992; Chem. Abstr.
1992, 117, 7735m.
(7) Recent examples: (a) Sakya, S. M.; Strohmeyer, T. W.; Lang, S.
A.; Lin, Y.-I Tetrahedron Lett. 1997, 38, 5913. (b) Annibalc, A. D.; Pesce,
A.; Resta, S.; Irogolo, C. T. Tetrahedron 1997, 53, 13129. (c) Alcaide,
B.; Polanco, C.; Sa´ez, E.; Sierra, M. A. J . Org. Chem. 1996, 61, 7125.
(d) Alcaide, B.; Rodr´ıguez-Vicente, A.; Sierra, M. A. Tetrahedron:
Asymmetry 1996, 7, 2203. (e) Banik, B. K.; Gottumukkala, V.; Manhas,
M. S.; Bose, A. K. Tetrahedron Lett. 1996, 37, 1363. (f) Chuansheng,
N.; Pettersson, T.; Miller, M. J . J . Org. Chem. 1996, 61, 1014. (g)
Crocker, P. J .; Miller, M. J . J . Org. Chem. 1995, 60, 6176. (h) Gilchrist,
T. L.; Graham, K. Tetrahedron Lett. 1995, 47, 8693. (i) Hanessian, S.;
Reddy, B. G. BioMed. Chem. Lett. 1994, 19, 2285.
(1) For a preliminary communication of a part of this work, see:
Alcaide, B.; Polanco, C.; Sierra, M. A. Tetrahedron Lett. 1996, 37, 6901.
(2) Biodi, S. In Anti-Infectives: Recent Advances in Chemistry and
Structure Activity Relationship; Bentley, P. H., O’Hanlon, P. J ., Eds.;
Special Publication No. 198; RSC: Cambridge, U.K., 1997; pp 86-
100.
(3) For excellent articles on the bacterian resistance to the common
use antibiotics, see: (a) Hook, V. Chem. Br. 1997, 33, 34. (b) Niccolai,
D.; Tarsi, L.; Thomas, R. J . Chem. Commun. 1997, 2333.
(4) Recent examples: (a) Wu, G.; Tormos, W. J . Org. Chem. 1997,
62, 6412. (b) Clader, J . W.; Burnett, D. A.; Caplen, M. A.; Domalski,
M. S.; Dugar, S.; Vaccaro, W.; Sher, R.; Browne, M. E.; Zhao, H.;
Burrier, R. E.; Salisbury, B.; Davis, H. R. J . Med. Chem. 1996, 39,
3684 and references therein.
(5) See, for example: Ojima, I. Adv. Asymmetric Synth. 1995, 1, 95.
S0022-3263(98)00114-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/15/1998

â-Lactam and Azetidine Systems
J . Org. Chem., Vol. 63, No. 20, 1998 6787
phile to form the tricyclic [4.5.6] skeleton in a single step.
Except for the polycyclic â-lactams built onto the penem
or cefem nuclei,10 the synthesis of other polycyclic 2-aze-
tidinones has been less investigated. Most of the re-
search in this field has focused onto benzo-fused carbap-
enem or carbacefem derivatives,11 as they are potential
suicide â-lactamase inhibitors. Other polycyclic systems
have been prepared by multistep synthesis directed
toward each specific type of compounds.7
The simultaneous construction of two of the three rings
of a tricyclic â-lactam system, on a preformed monocyclic
2-azetidinone, was at the beginning of this work a
conceptually different, straightforward, approach to this
type of compounds. Following this idea we devised the
Pauson-Khand (P-K) cyclization12 of enyne-2-azetidi-
nones to access to tricyclic â-lactams. This reaction was
chosen because it ranks among the best methods to
increase molecular complexity in a single synthetic step.
The idea of our original project was to gain access to all
possible modes of fusion on the four-membered ring,
starting from easily available precursors. In this paper
we report in full1 the scope of this approach to new
tricyclic â-lactam systems, as well as the extension of the
P-K cyclization to prepare new tricyclic azetidines.
Furthermore, the structural requisites for the P-K
reaction on a four-membered 2-azetidinone ring, to the
best of our knowledge unprecedented, will be also dis-
cussed.
Resu lts a n d Discu ssion
A series of enyne-2-azetidinones 1-7 (Figure 1) were
prepared to build tricyclic â-lactams by using the P-K
reaction, to study the scope of the approach and its regio-
and stereochemistry. Enyne imines 8 and 9 and D-
glyceraldehyde acetonide imines 10, prepared by stan-
dard aldehyde-amine condensation, were reacted with
(8) For an exhaustive revision on 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 on the application of
cyclization reactions to trinem and trinem derivatives synthesis: (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 .; 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.
(9) (a) Martel, S. R.; Wisedale, R.; Gallagher, L. D.; Mahon, F.;
Badbury, R. H.; Hales, N. J . J . Am. Chem. Soc. 1997, 119, 2309. (b)
Planchenault, D.; Wisedale, R.; Gallagher, T.; Hales, N. J . J . Org.
Chem. 1997, 62, 3438.
(10) 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 and pertinent
references therein.
(11) (a) J oyeau, R.; Yadav, L. D. S.; Wakselman, M. J . Chem. Soc.,
Perkin Trans 1 1987, 1899. (b) Finkelstein, J .; Holden, K. G.; Per-
chonock, C. D. Tetrahedron Lett. 1978, 1629. (c) Hakimelahi, G. H.;
J ust, G. Can. J . Chem. 1979, 57, 1939. (d) Bose, A. K.; Ram, B.;
Hoffman, N. A.; Hutchinson, A. J .; Manhas, M. S. J . Heterocycl. Chem.
1979, 16, 1313. (e) Miyake, H.; Tokutake, N.; Kirisawa, M. Synthesis
1983, 833. (f) Bachi, M. D.; Klein, J . J . Chem. Soc., Perkin Trans. 1
1983, 1925. (g) Hegedus, L. S.; McGuire, M. A.; Schultze, L. M.; Yijun,
C.; Anderson, O. P. J . Am. Chem. Soc. 1984, 106, 2680. (h) Ongania,
K. H.; Wallnoefer, M. Arch. Pharm. (Weinheim, Ger.) 1985, 318, 2.
(12) For reviews on the P-K reaction, see: (a) Schore, N. E. In
Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F.
G. A., Wilkinson, G., Eds.; Pergamon: Oxford, U.K., 1995; Vol. 12, p
703. (b) Schore, N. E. Org. React. 1991, 40, 1. (c) Pauson, P. L.
Tetrahedron 1985, 41, 5855.
F igu r e 1.
alkoxyacetyl chlorides in the presence of Et3N to yield
2-azetidinones 1a ,b, 2, and 11a -d , in good to excellent
yields and exclusively as cis-diastereomers. Compounds
11a -d was also single cis-enantiomers (ee > 95%).13
2-Azetidinones 1a ,b and 2 have the enyne moiety re-
quired carrying out the P-K reaction. However, com-
pounds 11a -d required further manipulation to obtain
the enyne functionality. Standard acetonide hydrolysis
to yield diols 12, followed by reaction with thiocarbon-
yldiimidazole (TCDI) in boiling THF14,15 and (MeO)3P15
yielded optically pure enyne-2-azetidinones 3a -d
(13) The cis-selectivity observed for compounds 1a ,b, 2, and 11a -d
was expected according to the current model for the Stau¨dinger
reaction. (a) Cossio, F. P.; Arrieta, A.; Lecea, B.; Ugalde, J . M. J . Am.
Chem. Soc. 1994, 116, 2085. (b) Hegedus, L. S.; Montgomery, J .;
Narukawa, Y.; Snustad, D. C. J . Am. Chem. Soc. 1991, 113, 5784. (c)
Palomo, C.; Aizpurua, J . M.; Mielgo, A.; Linden, A. J . Org. Chem. 1996,
61, 9186. This model accounts for
a 3R,4S stereochemistry for
D-glyceraldehyde-derived 2-azetidinones. For an experimental study
on the synthesis of 2-azetidinones derived from D- and L-glyceraldehyde
acetonide imines, see: (d) Hubschwerelen, C.; Schmid, G. Helv. Chim.
Acta 1983, 66, 2206. (e) Welch, J . T.; Araki, K.; Kawecki, R.; Wich-
towski, J . A. J . Org. Chem. 1993, 58, 2454. (f) 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.
(14) Corey, E. J .; Winter, R. A. E. J . Am. Chem. Soc. 1963, 85, 2677.
(15) Horton, D.; Turner, W. N. Tetrahedron Lett. 1964, 36, 2531.

6788 J . Org. Chem., Vol. 63, No. 20, 1998
Alcaide et al.
Sch em e 1
Sch em e 3
(Scheme 1). Alternatively, oxidative cleavage of diol 12e
(NaIO4/MeOH/H2O)16 obtained from 11e, formed 4-formyl-
2-azetidinone 13. Compound 13 was obtained as a
diasteromeric mixture of methoxy hemiacetals, which
were easily transformed to the free aldehyde by azeotro-
pic distillation using a Dean-Stark apparatus. Optically
pure aldehyde 13 was converted to the diastereomeric
mixture of enyne alcohols 5a by reaction with lithium
(trimethylsilyl)acetylide (THF, -78 °C) (Scheme 2). 2-Aze-
tidinone 5b having a terminal alkyne was prepared by
desilylation of compound 5a with Bu4NF.17
reaction of aldehyde 14a with methylenetriphenylphos-
phonium ylide formed â-lactam 4 (41%). Addition of
lithium (trimethylsilyl)acetylide to aldehydes 14b,c yielded
hydroxypropargyl derivatives 6a ,b in excellent yields and
as diastereomeric mixtures in the exocyclic stereogenic
center (Scheme 3). Treatment of compounds 6a ,b with
Bu4NF yielded 2-azetidinones 6c,d . Finally, racemic
2-azetidinone 7 was prepared from NH-4-acetoxy-2-
azetidinone and propargylmagnesium bromide, followed
by alkylation with allyl bromide according to the reported
procedure.19
Sch em e 2
With a variety of enyne-2-azetidinones in hand the
P-K reaction was tested next. Previous work from our
laboratories20 has shown that 2-azetidinones having a
N-propargyl-Co2(CO)6 moiety lost the propargyl group
when heated in the presence of wet DMSO. With these
results in mind, the behavior of Co2(CO)6-alkyne com-
plexes derived from compounds 2 and 3a with a N-
propargyl moiety attached to the lactam nitrogen or with
the triple bond directly bonded to the ring C4 position,
was tested. Reaction of compounds 2 and 3a with Co2-
(CO)8 at room temperature formed the corresponding
alkyne-Co2(CO)6 complexes quantitatively.21 These com-
plexes were reacted with the different promoters of the
P-K reaction, including heat (boiling toluene or ben-
zene),12 N-methylmorfoline N-oxide (NMO),22 trimethy-
lamine N-oxide (TMANO),23 and DMSO.24 Very complex
reaction mixtures were obtained in all cases. The sole
identifiable, trace products were the corresponding NH-
2-azetidinones. These results shown that the presence
Reaction of D-glyceraldehyde acetonide imines 10 with
crotonyl, 4-pentenoyl, and 4-pentinoyl chloride produced
sluggish reaction mixtures on the different reaction
conditions tested. Access to substrates 4 and 6 was
achieved from racemic aldehydes 14, prepared by reaction
of p-anisyl glyoxal diimine and the above acid chlorides,
following our previously reported procedure.18 Wittig
(19) (a) Nishida, A.; Shibasaki, M.; Ikegami, S. Tetrahedron Lett.
1981, 22, 4819. (b) Ziegler, C. B.; Curran, W. V.; Keigelson, G. B.; Bitha,
P.; Fabio, P.; Strohmeyer, T.; Short, K.; Liu, Y.-i. Tetrahedron 1994,
50, 12085.
(20) Alcaide, B.; Pe´rez-Castells, J .; Sa´nchez-Vigo, B.; Sierra, M. A.
Chem. Commun. 1994, 587.
(21) 2-Azetidinone-alkyne-Co2(CO)6 complexes can be isolated and
characterized. See the Supporting Information for one example.
(22) Examples: (a) Clive, D. L. J .; Cole, D. C.; Tao, Y. J . Org. Chem.
1994, 59, 1396-1406. (b) Chung, Y. K.; Lee, B. Y.; J eong, N.; Hudecek,
M.; Pauson, P. L. Organometallics 1993, 12, 220-223.
(23) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett.
1990 31, 5289.
(24) (a) DMSO: Chung, Y. K.; Lee, B. Y.; J eong, N.; Hudecek, M.;
Pauson, P. L. Organometallics 1993, 12, 220. (b) DMS: Stumpf, A.;
J eong, N.; Sunghee, H Synlett 1997, 205.
(16) 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.
(17) Corey, E. J .; Snider, D. B. J . Am. Chem. Soc. 1972, 94, 2459.
(18) 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.

â-Lactam and Azetidine Systems
J . Org. Chem., Vol. 63, No. 20, 1998 6789
of N-propargyl groups is not compatible with our ap-
proach. Compounds 3b, 4, and 7, lacking a propargyl
moiety, were tested next. Formation of the alkyne-Co2-
(CO)6 complexes occurred in quantitatively yield. Treat-
ment of such complexes with TMNO gave extremely clean
reaction mixtures, containing the desired tricyclic prod-
ucts 15-17a , as single diastereomers, and compound 15,
as a single enantiomer.25 Pure compounds 15-17a were
obtained by flash chromatography (Scheme 4). Other
promoters, such as boiling toluene, wet silica gel,26 and
NMO gave analogous results. Best yields were obtained
for compound 15 in boiling toluene while TMANO was
superior for compounds 16 and 17a . It should be pointed
out the exquisite selectivity of these reactions (see below
for configurational assignment). Compound 3c quanti-
tatively gave the corresponding alkyne-Co2(CO)6 com-
plex, which was unreactive in the different conditions
tested.
in the literature.27 Furthermore, while TMS derivative
6a -M gave a single diastereomer of the tricycle 18a , a
diastereomeric mixture (70:30) of compound 19a was
obtained from 6b-M. The analogous reaction of com-
plexes derived from terminal alkynes 5b-(M + m ) (as a
diastereomer mixture) and 6d -M (major diastereomer)
gave tricycles 17c and 19b. Surprisingly, the complex
derived from compound 6c-M was unreactive toward
cyclization and decomplexed 6c-M was recovered un-
changed. Other reaction conditions were tested to pro-
mote the cyclization of compound 6c-M, always with
negative results. The selectivity of the cyclizations of
compounds 5b-(M + m ) and 6d -M depends, again, on
the structure of the substrate. Thus, compound 5b-(M
+ m ) cyclized in almost quantitative yield, to give the
mixture of diastereomeric tricycles 17c, without changes
in the starting diastereomer ratio. Tricycles 17c were
now easily separated by flash chromatography, to give
both diastereomers of 17c as optically pure compounds
differing, exclusively, in the configuration of the carbon
bearing the hydroxyl group. Cyclization of azetidinone
6d -M gave a mixture of diastereomeric tricycles 19b (70:
30), with a selectivity analogous to the TMS derivative
6b-M. It appears to be that the selectivity is intrinsic to
the cyclization mode.
Sch em e 4
Sch em e 5
To extend this approach to the synthesis of many other
types of fused tricyclic 2-azetidinones, as well as to
determine its compatibility with the presence in the
molecule of a versatile functional group, compounds 5 and
6 having an hydroxypropargyl moiety were tested next.
Monocyclic TMS derivatives 5a -(M + m ) (as a mixture
of both isomers: M, major isomer; m, minor isomer) and
the separated major isomers of 2-azetidinones 6a -M and
6b-M were reacted first. In both cases the corresponding
alkyne-Co2(CO)6 complexes were obtained again without
novelty. Treatment of the complexes derived from 6a -M
and 6b-M with TMANO formed tricyclic derivatives 18a
and 19a , in low yields. In both cases considerable
amounts of decomplexed starting material were recov-
ered. The complex derived from 5a yielded only the
decomplexed starting 2-azetidinone 5a upon treatment
with TMANO. The hindered triple bond should be
responsible for the low yields obtained, a fact documented
Finally, although the difficulty to obtain ring sizes
higher than five or six by a P-K reaction is well-known,12
we tested this possibility on the complexes derived from
â-lactams 1a ,b. As expected, complex reaction mixtures
were obtained in the diverse conditions used. The sole
identifiable material was derived from the reduction of
the triple bond to the olefin on azetidinones 1a ,b, and it
was isolated in very low yield (8% and 17%, respectively).
(25) In all cases the diastereomer ratio was determined by integra-
tion of well-resolved signals in the 1H NMR spectra of the crude
reaction mixtures before purification.
(26) (a) Smit, W. D.; Kireev, S. L.; Nefedov, O. M.; Tarasov, V. A.
Tetrahedron Lett. 1989, 30, 4021-4024. (b) Gybin, A. S.; Smit, W. A.;
Caple, R.; Veretenov, A. L.; Shashkov, A. S.; Vorontsova. L. G.; Kurella,
M. G.; Chertkov, V. S.; Carapetyan, A. A.; Kosnikov, A. Y.; Alexanyan,
M. S.; Lindeman, S. V.; Panov, V. N.; Maleev, A. V.; Struchkov, Y. T.;
Sharpe, S. M. J . Am. Chem. Soc. 1992, 114, 5555.
(27) Mukai, C.; Uchiyama, U.; Sakamoto, S.; Hanaoka, M. Tetra-
hedron Lett. 1995, 36, 5761.

6790 J . Org. Chem., Vol. 63, No. 20, 1998
Alcaide et al.
Sch em e 6
Although unusual, the reduction of a triple bond under
P-K reaction conditions has been reported.28
Results above show that the P-K reaction is a simple
and, most of the times, an efficient entry to different
tricyclic 2-azetidinones with a five- or six-membered ring
fused to the â-lactam nucleus. Exceptions are those
monocyclic 2-azetidinones having an N-propargyl moiety.
These results are significative since amides having a
propargyl group form P-K derived products.29 It is well-
known that the 2-azetidinone ring with a pyramidalized
lactam nitrogen is unstable.30 Transition states leading
to tricyclic 2-azetidinones from alkyne-Co2(CO)6 com-
plexes are expected to have highly pyramidalized â-lac-
tam nitrogens. To test if this effect was responsible for
the failure of compounds 2 and 3a to form cyclized
derivatives, azetidines 20a ,b were prepared. The pla-
narity of the amide nitrogen, imposed by the amide
resonance, is excluded in azetidines. Additionally, due
to the interesting biological activity of some related
tricyclic azetidines,31 the study was extended to aze-
tidines 20c,d , derived from 2-azetidinones reactive to-
ward P-K cyclization. Azetidines 20 were easily pre-
pared by reduction of the corresponding â-lactams with
excess of AlH2Cl (generated in situ from LiAlH4/AlCl3)
following the procedure reported by Ojima.32 The reac-
tion was instantaneous at room temperature, and the
stereochemistry of the starting monolactams remained
unaltered during the process.
Azetidines 20 were reacted with Co2(CO)8 in solution
of DCM forming the corresponding complexes in quan-
titative yields. These complexes were submitted, without
isolation, to TMANO treatment at room temperature,
yielding, with the exception of azetidine 20c, the expected
tricyclic derivatives 21-23 (Scheme 6). The unstability
of both the azetidines 20, and of the final products,
precluded heating as a promoter for the P-K reaction.
Pure tricyclic azetidines 22 and 23 were obtained by flash
chromatography (hexane/Et3N mixtures). Compound 21
was unseparable from a new product lacking the azeti-
dine nucleus (see below). Azetidines 20a ,b yielded
exclusively a single diastereomer of the corresponding
tricyclic products, but compound 20d formed a 75:25
mixture of compound 23. Formation of compounds 21
and 22 from azetidines 20a ,b clearly demonstrated that
the lactam nitrogen is the responsible for the failure of
â-lactams 2 and 3a to form tricyclic 2-azetidinones. It
can be concluded that, for N-propargyl derivatives, the
amide resonance should both decrease the mobility on
the P-K intermediate and also force a planarity which
is not compatible with the cyclization process. A surpris-
ing result is the inertia of compound 20c toward cycliza-
tion. The different reaction conditions tested either
resulted in recovering of starting decomplexed material
or in formation of intractable reaction mixtures.
A
hypothesis to explain these results may be the anchorage
of the basic nitrogen to the coordination site to be filled
by the olefin double bond. This coordination should
inhibit the cyclization. The presence on compound 20c
of an additional methylene group, with respect to the
reactive azetidine 20b , may ensure an appropriate
geometry by placing the basic nitrogen close to the
unsaturated cobalt cluster. An analogous result was
obtained for the complex of TMS derivative of 20c. In
this case, standard TMNO treatment resulted in the
recovering of decomplexed starting material.
The reactivity of azetidine 20a deserves a special
comment. Sequential reaction of compound 20a with Co2-
(CO)8 and TMANO formed the desired tricycle 21.
However, a new product lacking the azetidine ring was
obtained (47% yield, pure material) together with azeti-
dine 21. NMR and analytical data for this new compound
were compatible with the bicyclic structure 24. To ensure
that compound 21 was not the precursor of bicycle 24,
the reaction mixture obtained from 20a was submitted
to the reaction conditions above. The composition of the
mixture remained unaltered through the process. For-
mation of compound 24 by azetidine ring breakage has
no precedents in the literature, except for our recent
report33 of an analogous process on azetidines having an
acetal or thiocetal attached to C2. These compounds
smoothly rearranged by N1-C2 bond breakage to bicyclic
pyrrolidines, upon treatment with AlEt2Cl. Azepine 24
may arise from a similar process. It is well-known the
(28) (a) Chisato, M.; Masahiko, U.; Miyoji, H. Chem. Commun. 1992,
1014. (b) Montan˜a, A. M.; Moyano, A.; Perica`s, M. A.; Serratosa, F.
An. Quim. 1987, 84, 82 and references therein.
(29) See, for example: (a) Clive, D. L. J .; Cole, D. C.; Tao, Y. J . Org.
Chem. 1994, 59, 1396. (b) Brown, S. W.; Pauson, P. L. J . Chem. Soc.,
Perkin Trans. 1 1990, 1205. (d) Becker, D. P.; Flynn, D. L. Tetrahedron
Lett. 1993, 34, 2087. (c) Yoo, S.-e.; Lee, S. H. J . Org. Chem. 1994, 59,
6968.
(30) For some selected examples reporting the bizarre effects caused
by the inhibition of NCdO resonance in amides, especially in the so-
called anti-Bredt amides, see: (a) Alcaide, B.; Casarrubios, L.; Domı´ngu-
ez, G.; Sierra, M. A.; Monge, A. J . Am. Chem. Soc. 1995, 117, 5604. (b)
Brouillette, W. J .; Einspahr, H. M. J . Org. Chem. 1984, 49, 5113. (c)
Collins, T. J .; Coots, R. J .; Furutani, T. T.; Keech, J . T.; Peake, G. T.;
Santarsiero, B. D. J . Am. Chem. Soc. 1986, 108, 5333. (d) Somayaji,
V.; Brown, R. S. J . Am. Chem. Soc. 1987, 109, 4738. (e) Somayaji, V.;
Skorey, K. I.; Brown, R. S. J . Org. Chem. 1986, 51, 4866. Slebocka-
Tilk, H.; Brown, R. S. J . Org. Chem. 1987, 52, 805. (f) Williams, R. M.;
Lee, B. H.; Miller, M. M.; Anderson, O. P. J . Am. Chem. Soc. 1989,
111, 1073.
(31) Reviews on the synthesis and chemistry of azetidines: (a) De
Kimpe, N. In Comprehensive Heterocyclic Chemistry II; Padwa, A.,
Eds.; Elsevier: Oxford, U.K., 1996; Vol. 1, Chapter 1.21.3. (b) Moore,
J . A.; Ayers, R. S. In Chemistry of Heterocyclic Compounds-Small Ring
Heterocycles; Hassner, A., Ed.; Wiley: New York, 1983; Part 3, pp
1-217. (c) Cromwell, N. H.; Phillips, B. Chem. Rev. 1979, 79, 331. To
the best of our knowledge, the sole precedent on the multistep synthesis
of tricyclic azetidines and their role as serotoninergic agents is by
Becker and Flynn: (d) Becker, D. P.; Flynn, D. L. Tetrahedron 1993,
49, 5047.
(32) Ojima, M.; Zhao, T.; Yamato, K.; Nakahashi J . Org. Chem.
1991, 56, 5263.
(33) Alcaide, B.; Salgado, N. R.; Sierra, M. A. Tetrahedron Lett. 1998,
39, 467.

â-Lactam and Azetidine Systems
J . Org. Chem., Vol. 63, No. 20, 1998 6791
Sch em e 7
F igu r e 2.
was assigned from compounds 17c, which are epimers
at the carbinol center. 1H NMR spectra were similar in
both epimers except, as expected, in the signals associ-
ated with H8. Thus, values of J 8,9 ) 1.7 Hz for 17c-M
and 4.7 Hz for 17c-m were measured, which are congru-
ent respectively with syn and anti stereochemistry
36
between both hydrogens.37
NOE irradiation on H8
resulted in complementary results for both isomers.
Thus, NOE enhancements of 4% were observed on H9
and H6 for 17c-M, while a 6% enhancement was observed
on H3 for compound 17c-m . It can be concluded that
compound 17c-M has a syn H8-H9/anti H8-H3 stere-
ochemistry, while compound 17c-m has an anti H8-H9/
syn H8-H3 stereochemistry. On the basis of analogous
data, an anti H3-H9 stereochemistry was established
for compound 17a . Stereochemistry for compound 15
was immediate by comparison with the above results.
Thus, the value of J 8,9 ) 7.5 Hz and a NOE enhancement
of 8% on H3 and the absence of NOE enhancement on
H9 upon irradiation of H8 ensure an anti H8-H9/syn
H8-H3 stereochemisty for this compound (Figure 3). It
is noteworthy that, for the epimers of 17c, the additional
carbinolic stereocenter has no influence in the stereo-
chemistry of the six-five ring junction.
The assignment of the stereochemistry of compounds
19a ,b, having the six-membered ring fused to the C3-
C4 bond of the â-lactam ring, was based on the major
isomer of compound 19b. Again, NOE irradiation of H3
resulted on enhancement of the signals corresponding to
H2, H5, and H8 (3, 4, and 4%, respectively), which is
consistent with an anti H3-H2/syn H3-H8 relative
stereochemistry. The J 2,3 ) 2.5 Hz is also consistent with
an anti H2-H3 stereochemistry in a pseudo-boat con-
formation. Analogous NOE enhancements were observed
between H2 and H3 in both isomers of compound 19a ;
J 2,3 was in the same range for both isomers, which
pointed to their nature of epimers at C8. However, NOE
enhancement was not observed for H8 in either isomer
of compound 19a when H3 was irradiated (Figure 4). It
may be concluded then that both isomers of compound
19a have an opposite stereochemistry at C8. The sense
of diastereoselectivity may be controlled by the stereo-
center contiguous to the olefin bond. However, these are
the sole cases in which a total diastereoselectivity was
not observed.
ability of Co clusters to stabilize carbocations on the
carbon contiguous to the metal.34 Intermediate 25 would
be formed after N1-C2 bond rupture, a process which
would relieve the steric energy of the crowded previous
intermediate. Formation of azepine 24 would end by
hydride capture from the reaction medium (Scheme 7).28
An alternative reaction pathway involving the interaction
of the basic azetidine nitrogen with the organometallic
cluster to promote the azetidine ring breakage has been
proposed by a reviewer. This is an appealing possibility
which cannot be disregarded with data in hand, since
formation of compound 24 would be closely related with
the azetidine ring breakage induced by AlEt2Cl. Al-
though much research will be necessary before ensuring
the generality of this process, it seems clear that the
presence of a N-propargyl moiety endows the azetidine
and 2-azetidinone nuclei with a special reactivity.
Con figu r a tion a l Assign m en t. The structure and
stereochemistry of compounds 15-19 and 21-23 have
been assigned by NMR techniques. The cis-stereochem-
isty of the four-membered ring is set during the cycliza-
tion step to form the 2-azetidinone ring, and it is
transferred unaltered during the further synthetic steps.
Compounds 16 and 18a showed values of J 2,3 and J 8,9 in
good agreement with those reported for analogous sys-
tems.35,36 Thus, a syn-stereochemistry for the hydrogens
of the central five-membered ring was assigned for
compound 16 with J 2,3 ) 4.8 Hz, while an anti-relative
disposition between H2 and H3 was assigned for com-
pound 18a with a J 2,3 ) 0 Hz. Furthermore, NOE-
irradiation of H2 on compound 16 resulted on 11%
enhancement on the signal corresponding to H3, which
is in agreement with the proposed cis-stereochemistry
(Figure 2). For compound 18a the analogous measure-
ment resulted in 3% enhancement, while irradiation of
H9 (J 8,9 ) 9.3 Hz) resulted in a 11% enhancement on the
signal corresponding to H8. Thus, a syn-stereochemisty
was established for this moiety.
(35) For clarity through this work tricyclic systems has been
numbered according with the numeration used for trinems. Thus, the
four-membered ring nitrogen has been assigned the locator 1 and the
remaining positions have been numbered to place the higher number
on the carbonyl group (for 2-azetidinones) or former carbonyl carbon
(for azetidines).
(36) (a) Galluci, J . C.; Ha, D.-C.; Hart, D. J . Tetrahedron 1989, 45,
1283. (b) Alcaide, B.; Esteban, G.; Mart´ın-Cantalejo, Y.; Plumet, J .;
Rodr´ıguez-Lo´pez, J . J . Org. Chem. 1994, 59, 7994.
Azetidinones 15, and 17a ,c have a six-membered ring
fused to the â-lactam. In these cases the stereochemisty
(34) Caffyn, A. J . M.; Nicholas, K. M. In Comprehensive Organo-
metallic Chemistry II; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.;
Pergamon Press: Oxford, U.K., 1995; Vol. 12, p 685.
(37) Gu¨nther, H. NMR Spectroscopy; J ohn Wiley and Sons: Chich-
ester, U.K., 1995.

6792 J . Org. Chem., Vol. 63, No. 20, 1998
Alcaide et al.
In conclusion, a synthetic approach to both racemic and
enantiomerically pure fused tricyclic 2-azetidinones and
azetidines has been developed by using a P-K reaction
as the key step. The process is highly diastereoselective
and allows one to prepare all the possible modes of ring
fusion. The exclusive limitation of this process is the
presence of an N-propargyl moiety attached to the
2-azetidinone ring. This structural feature is compatible
with azetidine cyclization, showing that the planarity
imposed by the amide group is responsible for the failure
of N-propargyl-2-azetidinones to cyclize. A potentially
interesting azetidine bond breakage has been disclosed.
To our knowledge this is the first time that a P-K
cyclization was studied with both the alkyne and the
alkene tethered to a heterocyclic four-membered ring.
Efforts to develop other cyclization approaches to fused
â-lactam and azetidine systems using 2-azetidinone
alkyne-Co2(CO)6 complexes are now underway.
F igu r e 4.
Exp er im en ta l Section
Gen er a l Meth od s. General experimental data and pro-
cedures have been previously reported.7c NMR spectra were
recorded in CDCl3 solutions, except otherwise stated. Chemi-
cal 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 deg
per dm at 20 °C, and the concentration (c) is expressed in g
per 100 mL in CHCl3. All commercially available compounds
were used without further purification. The following chemi-
cals were prepared according to literature procedures: 2,2-
Dimethyl-5-pentenal,38 4-butynamine,39 N,N-bis(p-methox-
yphenyl)diimine,40 2,3-O-(isopropylidene)-D-glyceraldehyde,41
propynal,42 3-ethenyl-4-formyl-1-(p-methoxyphenyl)-2-azetidi-
none.18
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
1a ,b, a n d 11a ,e. The corresponding alkoxyacetyl chloride (15
mmol) in anhydrous benzene (30 mL) was added dropwise via
syringe to a solution of the corresponding imine (10 mmol) and
Et3N (20 mmol) in benzene (30 mL) under argon. The
resulting mixture was stirred at room temperature until
complete disappearance of the imine (TLC). The crude mix-
ture was diluted with CH2Cl2 (40 mL) and washed with
saturated NaHCO3 (2 × 20 mL) and brine (40 mL). The
organic layer was dried (MgSO4) and the solvent removed
under vacuo. The crude compound was purified by flash
chromatography (EtOAc/hexanes mixtures) to yield analyti-
cally pure compounds 1 or 11. Spectroscopic and analytical
data for some representative forms of 1 and 11 follow.43
cis-3-(Ben zyloxy)-4-(1,1-d im eth yl-3-bu ten yl)-1-(2-p r o-
p yn yl)-2-a zetid in on e, 1a . From 2.98 g (2.0 mmol) of imine
8a and 5.47 g (3.0 mmol) of (benzyloxy)acetyl chloride, 5.64 g
(95%) of compound 1a was obtained as a colorless oil after
F igu r e 3.
The stereochemistry of tricyclic azetidines 22 and 23
was determined on the same basis (Figure 5). The
complexity of the spectra in these compounds required
the unambiguous elucidation of every proton, which was
done by two-dimensional techniques (COSY and/or HET-
COR). For compound 23, J 2,3 ) 5.8 Hz is in agreement
with a syn stereochemistry, by comparison with reported
data for related derivatives.31d NOE irradiation of H3
on compound 23 resulted in an 11% enhancement of the
signal corresponding to H2, which allows us to assign a
syn H2-H3 stereochemistry. Irradiation of H7 on com-
pound 22 did not produced any enhancement on H8,
which pointed to an anti relationship between both
hydrogens. Finally, the stereochemistry of compound 21
could not be determined due to the overlapping of the
significative signals with those of bicyclic azepine 24.
1
purification by flash chromatography (1/6 hexane/AcOEt). H
NMR: δ 1.07 (s, 6 H), 2.25 (dd, 1 H, J ) 13.5, 7.7 Hz), 2.27 (s,
1 H), 2.30 (dd, 1 H, J ) 13.5, 7.7 Hz), 3.65 (d, 1 H, J ) 5.3
Hz), 3.79 (dd, 1 H, J ) 17.7, 2.1 Hz), 4.39 (dd, 1 H, J ) 17.7,
2.1 Hz), 4.69 (d, 1 H, J ) 5.3 Hz), 4.68 (d, 1 H, J ) 11.9 Hz),
4.95 (d, 1 H, J ) 11.9 Hz), 4.94-5.09 (m, 2 H), 5.76-5.94 (m,
(38) Salomon, R. G.; Ghosh, S. Organic Syntheses; Wiley: New York,
1990; Collect. Vol. VII, p 177.
(39) Dumont, J . L.; Chodkiewicz, W.; Cadiot, P Bull. Soc. Chim. Fr.
1967, 2, 588.
(40) (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.
(41) 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.
(42) Sauer, J . C. Organic Syntheses; Wiley: New York, 1993; Collect.
Vol. IV, p 813.
(43) Full spectroscopic and analytical data for compounds not
included in this Experimental Section are described in the Supporting
Information.
F igu r e 5.

â-Lactam and Azetidine Systems
J . Org. Chem., Vol. 63, No. 20, 1998 6793
1 H), 7.26-7.36 (m, 5 H). 13C NMR: δ 168.8, 137.4, 134.5,
128.5, 127.9, 127.7, 118.2, 82.4, 76.7, 73.3, 73.2, 65.9, 43.8, 36.3,
31.4, 24.9, 23.4. IR (CHCl3): ν 3300, 1750, 1640. Anal. Calcd
for C19H23NO2: C, 76.74; H, 7.80; N, 4.71. Found: C, 76.53;
H, 8.03; N, 4.50.
1 H, J ) 2.7, 0.6 Hz), 2.37-2.45 (m, 2 H), 3.16 (dt, 1 H, J )
13.9, 7.0 Hz), 3.49 (dt, 1 H, J ) 13.9, 7.0 Hz), 4.26 (dd, 1 H, J
) 8.7, 4.5 Hz), 4.63 (d, 1 H, J ) 11.4 Hz), 4.65 (d, 1 H, J )
11,4 Hz), 4.75 (d, 1 H, J ) 4.5 Hz), 5.38-5.46 (m, 2 H), 5.86-
5.95 (m, 1 H), 7.23-7.32 (m, 5 H). 13C NMR: δ 166.9, 136.8,
132.7, 128.5, 128.2, 128.1, 122.3, 83.0, 81.0, 72.6, 70.4, 61.7,
38.9, 18.3. IR (CHCl3): ν 3320, 1760, 1710. Anal. Calcd for
(+)-(3R,4S)-3-(Ben zyloxy)-4-[(S)-2,2-d im eth yl-1,3-d iox-
ola n -4-yl]-1-(2-p r op yn yl)-2-a zetid in on e, (+)-11a . From
3.34 g (2.0 mmol) of imine 10a and 5.47 g (3.0 mmol) of
(benzyloxy)acetyl chloride, 3.28 g (52%) of compound (+)-11a
was obtained as a colorless crystalline solid after purification
by flash chromatography (1/6 EtOAc/hexane). Mp: 64-65 °C
(AcOEt/hexanes). [R]D ) +76.3 (c ) 1.0, CHCl3). 1H NMR: δ
1.32 (s, 3 H), 1.46 (s, 3 H), 2.22 (t, 1 H, J ) 2.4 Hz), 3.68 (dd,1
H, J ) 4.8, 8.7 Hz), 3.79 (dd, 1 H, J ) 9.3, 5.4 Hz), 3.87 (dd,
1 H, J ) 17.4, 2.4 Hz), 4.10 (dd, 1 H, J ) 6.6, 8.7 Hz), 4.38
(dd, 1 H, J ) 17.4, 2.4 Hz), 4.33-4.47 (m, 1 H), 4.61 (d, 1 H,
J ) 11.7 Hz), 4.61 (d, 1 H, J ) 5.4 Hz), 4.89 (d, 1 H, J ) 11.7
Hz), 7.28-7.30 (m, 5 H). 13C NMR: δ 167.0, 136.9, 128.6,
128.2, 127.9, 117.6, 109.9, 80.7, 76.9, 73.1, 72.2, 66.8, 59.3, 30.7,
C
16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.31; H,
6.54; N, 5.27.
(+)-(3R,4S)-3-(Ben zyloxy)-1-(4-p en tyn yl)-4-vin yl-2-a ze-
tid in on e, (+)-3c. From 1.72 g (5.0 mmol) of compound 11c,
0.86 g (67%) of compound (+)-3c was obtained as a colorless
oil after purification by flash chromatography (5/1 hexane/
EtOAc). [R]D ) +22.8 (c ) 1.0, CHCl3). 1H NMR: δ 1.56-
1.77 (m, 2 H), 1.90 (t, 1 H, J ) 2.6 Hz), 2.11-2.16 (m, 2 H),
3.04-3.26 (m, 1 H), 3.28-3.42 (m, 1 H), 4.05 (dd, 1 H, J )
8.8, 4.4 Hz), 4.52-4.61 (AB, 2 H, J ) 14.7 Hz), 4.66 (d, 1 H, J
) 4.4 Hz), 5.22-5.39 (m, 2 H), 5.38-5.89 (m, 1 H), 7.21-7.27
(5 H). 13C NMR: δ 167.1, 136.9, 132.9, 128.5, 128.2, 128.1,
122.1, 82.9, 82.8, 72.6, 69.3, 61.6, 39.5, 26.6, 16.3. IR
(CHCl3): ν 3315, 1760, 1715. Anal. Calcd for C17H19NO2: C,
75.81; H, 7.11; N, 5.20. Found: C, 76.15; H, 6.74; N, 5.41.
(+)-(3R,4S)-3-P h en oxy-(1-p r op yn yl)-4-vin yl-2-a zetid i-
n on e, (+)-3d . From 1.52 g (5.0 mmol) of compound 11d , 0.63
g (55%) of compound (+)-3c was obtained as a colorless oil
after purification by flash chromatography (6/1 hexane/EtOAc).
[R]D ) +10.1 (c ) 0.1, CHCl3). 1H NMR: δ 2.26 (t, 1 H, J )
2.7 Hz), 3.73 (dd, 1 H, J ) 2.7, 17.7 Hz), 4.33 (dd, 1 H, J )
2.7, 17.7 Hz), 4.50 (dd, 1 H, J ) 4.5, 8.7 Hz), 5.29 (d, 1 H, J )
4.5 Hz), 5.35-5.51 (m, 2 H), 5.81-5.93 (m, 1 H), 6.9-7.3 (m,
5 H). 13C NMR: δ 164.7, 157.3, 130.86, 129.62, 123.2, 122.4,
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, 73.78; H, 5.51; N, 6.00.
(+)-(3R,4S)-4-F or m yl-3-p h en oxy-1-(2-p r op en yl)-2-a ze-
tid in on e, (+)-13. To a solution of the â-lactam 11e (4.02 g,
13.0 mmol) in THF/H2O (1/1, 200 mL) was added solid p-TsOH‚
H2O (1,83g, 14.3 mmol) in a single portion. The resulting
solution was then refluxed until complete disappearance of the
starting material. The reaction mixture was allowed to cool
to room temperature, the THF was removed under vacuo, and
the aqueous residue was neutralized with solid NaHCO3. The
mixture was extracted with CH2Cl2 (3 × 20 mL), and the
organic layer was dried (MgSO4). The solvent was removed
under vacuo, and the resulting oil was dissolved in 150 mL of
1/1 MeOH/H2O. NaIO4 (20 mmol) was added to this solution,
and the mixture was maintained below 20 °C and stirred
vigorously until total disappearance of the starting material
(TLC). The reaction mixture was diluted with water and
extrated with CH2Cl2 (3 × 50 mL) and dried (MgSO4). After
removal of the solvent under vacuo the crude was dissolved
in benzene and refluxed with a Dean-Stark apparatus for 2
h. Evaporation of the solvent under vacuo yielded 2.97 g (97%)
of pure aldehyde (+)-13 as a colorless oil. [R]D ) +59.4 (c )
1.0, CHCl3). 1H NMR: δ 3.87 (dd, 1 H, J ) 15.3, 7.2 Hz), 3.97
(dd, 1 H, J ) 14.8, 6.0 Hz), 4.30 (dd, 1 H, J ) 5.1, 2.4 Hz),
5.13-5.19 (m, 2 H), 5.36 (d, 1 H, J ) 5.1 Hz), 5.63-5.72 (m, 1
H), 6.83-6.98 (m, 2 H), 7.17-7.22 (m, 3 H), 9.59 (d, 1 H, J )
2.4 Hz). 13C NMR: δ 197.2, 164.3, 156.7, 130.3, 129.6, 122.9,
120.4, 115.4, 82.0, 63.2, 44.4. IR (CHCl3): ν 1780, 1740, 1600.
Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06.
Found: C, 67.87; H, 5.35; N, 6.38.
27.0, 25.3. IR (CHCl3): ν 3230, 1770. Anal. Calcd for C18H21
-
NO4: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.77; H, 6.42; N,
4.71.
(+)-(3R,4S)-4-[(S)-2,2-Dim eth yl-1,3-dioxolan -4-yl]-3-ph e-
n oxy-1-(2-p r op en -yl)-2-a zetid in on e, (+)-11e. From 3.38 g
(2.0 mmol) of imine 10d and 5.12 g (3.0 mmol) of phenoxyacetyl
chloride, 4.48 g (74 %) of compound (+)-11e was obtained as
a pale yellow oil after purification by flash chromatography
(1/6 EtOAc/hexane). Mp: 63-65 °C (AcOEt/hexanes). [R]D
)
+100.9 (c ) 1.1, CHCl3). 1H NMR: δ 1.37, (s, 3 H), 1.44 (s, 3
H), 3.38 (dd, 1 H, J ) 8.8, 5.9 Hz), 3.77-3.87 (m, 2 H), 4.12-
4.24 (m, 2 H), 4.41-4.48 (m, 1 H), 5.20 (d, 1 H, J ) 5.2 Hz),
5.22-5.28 (m, 2 H), 5.68-5.82 (m, 1 H), 6.98-7.07 (m, 3 H),
7.26-7.33 (m, 2 H) . 13C NMR: δ 165.6, 157.3, 131.2, 129.6,
129.5, 122.5, 118.9, 109.7, 79.9, 77.1, 66.9, 59.8, 44.0, 26.8, 25.2.
IR (KBr): ν 1760, 1600. Anal. Calcd for C17H21NO4: C, 67.31;
H, 6.98; N, 4.62. Found: C, 67.65; H, 6.51; N, 4.33.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
3a -d . To a solution of the corresponding â-lactam 11 (10
mmol) in THF/H2O (1:1, 200 mL) was added solid p-TsOH‚H2O
(12 mmol) in a single portion. The resulting clear solution was
refluxed until complete disappearance of the starting material.
The reaction mixture was allowed to cool to room temperature,
the THF was removed under vacuo, and the aqueous residue
was neutralized with solid NaHCO3. The mixture was ex-
tracted with CH2Cl2 (3 × 20 mL), and the organic layer was
dried (MgSO4). The solvent was removed under vacuo, and
the residue was dissolved in 150 mL of THF. 1,1-Thiocarbo-
nyldiimidazole (12 mmol) was added to this solution, and the
mixture was refluxed until the starting material disappeared
(TLC). The reaction mixture was diluted with CH2Cl2 and
dried (MgSO4). After removal of the solvent under vacuo, the
obtained thiocarbonate was used in the next step without
purification. A solution of thiocarbonate in (MeO)3P (30 mL)
was refluxed until the starting product was consumed (TLC).
The solvent was then evaporated under vacuo and the reaction
crude was purified by flash chromatography (4:1 hexanes/
EtOAc) affording the expected, analytically pure, 4-vinyl-2-
azetidinones 3a -d as pale yellow oils.
(+)-(3R,4S)-3-Ben zyloxy-1-(2-p r op yn yl)-4-vin yl-2-a ze-
tid in on e, (+)-3a . From 3.28 g (10.0 mmol) of compound 11a ,
2.02 g (84%) of compound (+)-3a was obtained as a colorless
oil after purification by flash chromatography (6/1 hexane/
EtOAc). [R]D ) +54.1 (c ) 3.0, CHCl3).1H NMR: δ 2.23 (t, 1
H, J ) 2.7 Hz), 3.69 (dd, 1 H, J ) 17.4, 2.7 Hz), 4.26 (m, 2 H),
4.56 (d, 1 H, J ) 15.6 Hz), 4.60 (d, 1 H, J ) 15.6 Hz), 4.76 (d,
1 H, J ) 4.8 Hz), 5.43-5.48 (m, 2 H), 5.90-5.97 (m, 1 H), 7.26-
7.35 (m, 5 H). 13C NMR: δ 166.2, 136.7, 131.9, 128.5, 128.2,
128.18, 122.5, 83.1, 76.4, 72.73, 72.70, 60.6, 29.3. IR (CHCl3):
ν 3000, 1750. Anal. Calcd for C15H15NO2: C, 74.67; H, 6.27;
N, 5.80. Found: C, 74.32; H, 6.06: N, 6.11.
cis-1-(p-Meth oxyp h en yl)-3-(2-p r op yn yl)-4-vin yl-2-a ze-
tid in on e, 4. BuLi (1.5 mL, 1.6 M in hexanes) was added to a
slurry of PPh3CH2I (0.85 g, 2.1 mmol) in anhydrous THF (6
mL) under argon. The resulting mixture was stirred at room
temperature during 0.5 h, and 2-azetidinone 14a (0.32 g, 1
mmol) in anhydrous THF (5 mL) was added dropwise via
syringe. The mixture was stirred at room temperature for 2
h. The reaction was then quenched with NH4Cl (3 mL,
saturated solution) and extracted with AcOEt (4 × 10 mL).
The organic layers were dried (MgSO4), and the solvent was
removed under vacuo. The residue was chromatographied
(EtOAc/hexanes) to yield 0.13 g (41%) of pure compound 4 as
a colorless crystalline solid. Mp: 73-75 °C (EtOAc/hexanes).
(+)-(3R,4S)-3-(Ben zyloxy)-1-(3-bu tyn yl)-4-vin yl-2-a ze-
tid in on e, (+)-3b. From 3.56 g (10.4 mmol) of compound 11b,
1.70 g (64%) of compound (+)-3b was obtained as a colorless
oil after purification by flash chromatography (6/1 hexane/
EtOAc). [R]D ) +23.8 (c ) 1.0, CHCl3). 1H NMR: δ 1.99 (td,

6794 J . Org. Chem., Vol. 63, No. 20, 1998
Alcaide et al.
1H NMR: δ 1.94 (t, 1 H, J ) 2.5 Hz), 2.35-2.45 (m, 1 H), 2.52-
2.62 (m, 1 H), 3.49-3.57 (m, 1 H), 3.69 (s, 3 H), 4.57 (t, 1 H,
J ) 5.9 Hz), 5.29-5.45 (m, 2 H), 5.89-6.01 (m, 1 H), 6.76 (d,
2 H, J ) 8.4 Hz), 7.25 (d, 2 H, J ) 8.4 Hz). 13C NMR: δ 164.8,
156.2, 132.0, 131.4, 121.2, 118.4, 114.3, 80.9, 70.2, 56.8, 55.6,
52.3, 15.0. IR (CHCl3): ν 3300, 1740, 1700, 1510. Anal. Calcd
for C15H15NO2: C, 74.65; H, 6.27; N, 5.81. Found: C, 74.48;
H,6.53; N, 5.67.
Syn th esis of 4-(1-h ydr oxy-3-tr im eth ylsilyl-2-pr opyn yl)-
2-a zetid in on es, 5a a n d 6a -b. BuLi (1.3 mmol, 1.6 M in
hexane) was added dropwise via syringe to a cooled (0 °C)
solution of (trimethylsilyl)acetylene (1.3 mmol) in anhydrous
THF (5 mL) under argon. After 15 min, the resulting solution
was transferred via cannula to a cooled solution (-78 or 0 °C)
of the corresponding â-lactam (1 mmol) in anhydrous THF (5
mL) by using argon pressure. The resulting mixture was
stirred until complete disappearance of the starting material
(TLC). The crude mixture was quenched with saturated
aqueous NH4Cl solution and dried (MgSO4). Solvent was
removed in vacuo, and the crude compound was purified by
flash chromatography.
cis-4-(1-Hyd r oxy-3-(tr im eth ylsilyl)-2-p r op yn yl)-3-p h e-
n oxy-1-(2-p r op en yl)-2-a zetid in on e, 5a . From 0.46 g (2.0
mmol) of aldehyde (+)-13 cooled to 0 °C after 15 min a crude
mixture containing both cis-diastereomers (75/25) was ob-
tained. From this mixture, 0.63 g (96%) of an inseparable
mixture of both diastereomers was obtained as colorless oil
after purification by flash chromatography (1/4 EtOAc/hexane).
Ma jor Isom er . 1H NMR: δ -0.06 (s, 9 H), 2.59 (d, 1 H, J
) 4.8 Hz), 3.80 (dd, 1 H, J ) 15.6, 6.9 Hz), 4.05 (t, 1 H, J )
4.8 Hz), 4.20 (ddt, 1 H, J ) 15.6, 5.4, 1.5 Hz), 4.70 (t, 1 H, J )
4.5 Hz), 5.16-5.26 (m, 3 H), 5.70-5.87 (m, 1 H), 6.92-7.05
(m, 3 H), 7.18-7.30 (m, 2 H). 13C NMR: δ 165.7, 157.4, 131.4,
129.6, 122.8, 118.9, 116.0, 102.6, 92.1, 81.5, 61.7, 60.7, 44.0,
-0.4.
tained as white solids after purification by flash chromatog-
raphy (1/6 EtOAc/hexane). Combined yield: 0.38 g (75%). The
major isomer was obtained as a pure compound after crystal-
ization (EtOAc/hexane).
Ma jor Isom er . White solid. Mp 74-75 °C. Yield: 0.30 g
(59%). 1H NMR: δ 0.15 (s, 9 H), 2.43 (d, 1 H, J ) 7.1 Hz),
2.60-2.81 (m, 2 H), 3.45 (td, 1 H, J ) 7.4, 5.9 Hz), 3.75 (s, 3
H), 4.34 (t, 1 H, J ) 5.3 Hz), 4.73 (dd, 1 H, J ) 7.1, 5.3 Hz),
5.09 (dd, 1 H, J ) 10.3, 1.1 Hz), 5.17 (dd, 1 H, J ) 17.2, 1.5
Hz), 5.89-6.02 (m, 1 H), 6.78-6.83 (d, 2 H), 7.41-7.51 (d, 2
H). 13C NMR: δ 167.5, 156.4, 135.9, 131.1, 120.1, 116.8, 114.1,
103.8, 93.2, 61.8, 58.7, 55.6, 51.0, 29.0, -0.3. IR (KBr): ν 3360
(broad), 1720, 1640. Anal. Calcd for C19H25NO3Si: C, 66.44;
H, 7.34; N, 4.08. Found: C, 66.79; H, 7.12; N, 4.17.
1-(2-P r op en yl)-4-(2-p r op yn yl)-2-a zetid in on e, 7. NaH
(0.2 g ca 5 mmol, 60% dispersion in mineral oil) was placed in
a round botton flask and washed three times with anhydrous
hexane under argon. Anhydrous THF (5 mL) was added via
syringe, and the resulting slurry was cooled to 0 °C (ice bath).
4-Propargyl-2-azetidinone (0.22 g, 2 mmol) in THF (3 mL) and
allyl bromide (0.29 g, 2.4 mmol) in THF (3 mL) were added
sequentially to this slurry dropwise via syringe. The reaction
mixture was stirred 20 min at 0 °C, and anhydrous DMF (0.4
mL) was added via syringe. The cooling bath was removed,
and the reaction was stirred 12 h at room temperature. The
resulting mixture was quenched with 1 N HCl (2 mL) and
water (5 mL). The mixture was extracted with EtOAc (3 ×
10 mL). The organic layer was washed with brine and dried
(MgSO4). The solvent was removed under vacuo, and the
residue was purified by chromatography to yield 0.23 g (77%)
of pure compound 7 as a viscous colorless oil. 1H NMR: δ 2.07
(t, 1 H, J ) 2.7 Hz), 2.53-2.57 (m, 2 H), 2.80 (dd, 1 H, J ) 14,
2.0 Hz), 3.07 (dd, 1 H, J ) 14.7, 4.8 Hz), 3.67-3.78 (m, 2 H),
4.02 (ddt, 1 H, J ) 15.6, 5.4, 1.2 Hz), 5.17-5.89 (m, 2 H), 5.70-
5.87 (m, 1 H). 13C NMR: δ 166.5, 132.1, 118.6, 81.1, 71.5, 49.2,
44.3, 41.9, 22.6. IR (CHCl3): ν 3300, 1740, 1660, 1640. Anal.
Calcd for C9H11NO: C, 72.46; H, 7.43; N, 9.39. Found: C,
72.58; H, 7.32; N, 9.65.
Gen er a l P r oced u r e for th e Syn th esis of Tr icyclic
2-Azetid in on es 15-19. Meth od A. Solid Co2(CO)8 (0.21 g,
0.6 mmol) was added to a solution of the corresponding
2-azetidinone (0.12 g, 0.5 mmol) in anhydrous CH2Cl2 (7 mL)
under argon. The dark solution thus obtained was stirred at
room temperature until complete complex formation by TLC
(ca. 1 h) The resulting solution of Co2(CO)6-alkyne complex
was cooled to 0 °C, and solid anhydrous TMANO (0.08 g, 1
mmol) was added. The reaction flask was open to the air and
warmed to room temperature by immediate removal of the ice
bath. After 30 min, the reaction was again cooled to 0 °C, 0.08
g (1 mmol) of solid anhydrous TMANO was added, and the
solution was warmed again to room temperature by immediate
removal of the ice bath. This sequence was repeated until a
total of 3 mmol (0.24 g) of anhydrous TMANO was added. After
that the solution was stirred for 1 h at room temperature.
During this period a purple precipitate was formed. TLC
analysis indicated the complete consumption of the starting
material and the formation of a more polar, UV active spot.
The crude mixture was diluted with AcOEt (20 mL) and
filtrated through a short path of Celite. The solvent was
removed under vacuo, and a colorless solid was obtained. The
cyclic compounds were purified by chromatography or crystal-
lization, as indicated in each case.
Min or Isom er . 1H NMR: δ -0.08 (s, 9 H), 2.76 (d, 1 H, J
) 8.1 Hz), 3.87 (dd, 1 H, J ) 15.3, 6.9 Hz), 3.97 (t, 1 H, J )
5.0 Hz), 4.10 (ddt, 1 H, J ) 15.3, 5.1, 1.5 Hz), 4.68 (dd, 1 H, J
) 8.1, 5.0 Hz), 5.16-5.26 (m, 3 H), 5.70-5.87 (m, 1 H), 6.92-
7.05 (m, 3 H), 7.18-7.30 (m, 2 H). 13C NMR: δ 165.7, 157.4,
131.2, 129.7, 122.9, 119.3, 116.3, 102.5, 92.6, 81.6, 61.1, 60.2,
43.3, -0.4. IR (CHCl3): ν 3560, 2410, 1760, 1600, 1500. Anal.
Calcd for C18H23NO3Si: C, 65.62; H, 7.04; N, 4.25. Found: C,
65.90; H, 6.88; N, 4.01.
cis-4-(1-H yd r oxy-3-(t r im et h ylsilyl)-2-p r op yn yl)-1-(p -
m eth oxyp h en yl)-3-vin yl-2-a zetid in on e, 6a . From 0.90 g
(1.5 mmol) of compound 14b at -78 °C after 2 h a crude
mixture containing both cis-diastereomers (78/22) was ob-
tained. Both isomers were separated as pure compounds after
chromatography (1/6 EtOAc/hexane). Combined yield: 0.79
g (82%).
Ma jor Isom er . White solid: Mp 94-96 °C (EtOAc/hexane).
1H NMR: δ 0.1 (s, 9 H), 2.72 (d, 1 H, J ) 6.3 Hz), 3.92 (s, 3
H), 3.96 (dd, 1 H, J ) 6.0, 6.9 Hz), 4.31 (t, 1 H, J ) 5.9 Hz),
4.53 (t, 1 H, J ) 6.1 Hz), 5.26-5.43 (m, 2 H), 5.94-6.08 (m, 1
H), 6.62-6.78 (d, 2 H), 7.38-7.47 (d, 2 H). 13C NMR: δ 165.7,
156.4, 132.8, 129.1, 121.9, 119.8, 114.9, 103.3, 93.0, 62.8, 59.4,
55.5, 55.1, -0.5. IR (CHCl3): ν 3400 (broad), 1750, 1520.
Anal. Calcd for C18H23NO3Si: C, 65.62; H, 7.04; N, 4.25.
Found: C, 65.97; H, 6.88; N, 4.49.
Min or Isom er . White solid: Mp 79-81 °C (EtOAc/hexane).
1H NMR: δ 0.0 (s, 9 H), 2.21 (s broad, 1 H), 3.69 (s, 3 H), 4.02
(dd, 1 H, J ) 7.8, 5.8 Hz), 4.27 (dd, 1 H, J ) 5.8, 3.5 Hz), 4.68
(d, 1 H, J ) 3.0 Hz), 5.29 (d, 1 H, J ) 10.3 Hz), 5.43 (d, 1 H,
J ) 17.2 Hz), 6.09 (ddd, 1 H, J ) 17.2, 10.3, 7.8 Hz), 6.75-
6.79 (d, 2 H), 7.33-7.38 (d, 2 H). 13C NMR: δ 165.1, 156.3,
130.7, 129.0, 121.8, 119.7, 114.2, 102.1, 94.3, 61.5, 59.1, 55.4,
55, -0.6. IR (CHCl3): ν 3600, 3400, 2405, 1750. Anal. Calcd
for C18H23NO3Si: C, 65.62; H, 7.04; N, 4.25. Found: C, 65.31;
H, 7.27; N, 4.39.
Meth od B. Solid Co2(CO)8 (0.21 g, 0.6 mmol) was added
to a solution of the corresponding 2-azetidinone (0.5 mmol) in
anhydrous toluene (7 mL) under argon. The dark solution was
stirred at room temperature until complete complex formation
by TLC (ca. 1 h). The resulting solution of Co2(CO)6-alkyne
complex was refluxed for 2 h. The solution was diluted with
AcOEt (20 mL), filtered through Celite, and concentrated
under reduced pressure. The solid residue was crystallized
(AcOEt).
Tr icyclic 2-Azetid in on e (+)-15. Meth od B. From 0.13
g of 2-azetidinone (+)-3b (0.5 mmol), 0.14 g (95%) of (+)-15
was obtained as a colorless solid after crystallization (AcOEt).
Mp: 108-110 °C. [R]D ) +83.6 (c ) 1.0, CHCl3). 1H NMR:
cis-4-(1-H yd r oxy-3-(t r im et h ylsilyl)-2-p r op yn yl)-1-(p -
m eth oxyp h en yl)-3-(2-p r op en yl)-2-a zetid in on e, 6b. From
0.37 g (1.5 mmol) of compound 14c at -78 °C after 90 min a
crude mixture containing both cis-diastereomers (75/25) was
obtained. From this mixture, both diastereomers were ob-

â-Lactam and Azetidine Systems
J . Org. Chem., Vol. 63, No. 20, 1998 6795
δ 1.97 (dd, 1 H, J ) 19.2, 2.1 Hz), 2.47 (dd, 1 H, J ) 18.7, 6.6
Hz), 2.46-2.58 (m, 1 H), 2.75-2.89 (m, 2 H), 3.09 (t, 1 H, J )
7.2 Hz), 3.31 (dd, 1 H, J ) 9.1, 3.9 Hz), 4.07-4.15 (m, 1 H),
4.60 (d, 1 H, J ) 11.7 Hz), 4.81 (d, 1 H, J ) 11.7 Hz), 4.80 (d,
1 H, J ) 9.1 Hz), 6.05 (s, 1 H), 7.22-7.35 (m, 5 H). 13C NMR:
δ 207.4, 177.1, 165.3, 136.9, 130.9, 129.0, 128.8, 128.4, 83.7,
73.7, 61.5, 39.9, 39.5, 38.1, 29.8. IR (CHCl3): ν 1760, 1710,
1400. Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94.
Found: C, 72.29; H, 6.24; N, 5.14. EIMS: m/ z 283 (parent),
254, 192, 164, 136, 108, 91, 65.
Tr icyclic 2-Azetid in on e 16. Meth od A. From 0.12 g of
2-azetidinone 4 (0.5 mmol), 0.11 g (80%) of 15 was obtained
as colorless solid after crystallization (EtOAc/hexanes). Mp:
159-160 °C. 1H NMR: δ 2.15 (dd, 1 H, J ) 17.7, 3.9 Hz),
2.46 (dd, 1 H, J ) 17.7, 6.6 Hz), 2.61 (dd, 1 H J ) 16.5, 9.9
Hz), 3.08-3.14 (d, 2 H), 3.69 (s, 3 H), 3.92 (dd, 1 H, J ) 9.6,
3.9 Hz), 4.53 (t, 1 H, J ) 4.8 Hz), 6.04 (s broad, 1 H), 6.74 (d,
2 H, J ) 9.5), 7.17 (d, 2 H, J ) 9.5 Hz). 1H NMR(DMSO-d6):
δ 1.86 (dd, 1 H, J ) 17.8, 3.7 Hz), 2.43-2.53 (m, 1 H), 2.78
(dd, 1 H, J ) 16.2, 9.7 Hz), 2.90 (d, 1 H, J ) 16.3 Hz), 3.30-
3.38 (m, 1 H), 3.71 (s, 3 H), 4.01 (dd, 1 H, J ) 8.5, 4.3 Hz),
4.75 (t, 1 H, J ) 4.6 Hz), 6.11 (s, 1 H), 6.91 (d, 2 H), 7.28 (d,
2 H). 13C NMR: δ 209.7, 181.8, 165.2, 156.6, 131.4, 129.3,
118.3, 114.7, 55.6, 55.0, 54.3, 46.8, 38.6, 28.4. IR (CHCl3): ν
1740, 1705, 1640. Anal. Calcd for C16H15NO3: C, 71.36; H,
5.61; N, 5.20. Found: C, 71.49; H, 5.50; N, 4.98. EIMS: m/ z
269, 240, 213, 212, 149, 134, 91 (parent), 65.
Tr icyclic 2-Azetid in on e 17a . Meth od A. From 0.15 g
(1.0 mmol) of 2-azetidinone 7, 0.11 g (65%) of compound 17
was obtained as a colorless solid after crystallization (EtOAc/
hexane). Mp: 154-155 °C. 1H NMR: δ 1.88 (dd, 1 H, J )
18.9, 1.8 Hz), 2.18 (t., 1 H, J ) 12.0 Hz), 2.34-2.45 (m, 2 H),
2.66 (dd, 1 H, J ) 15.0, 1.8 Hz), 2.73-2.76 (m, 1 H), 3.05-
3.16 (m, 2 H), 3.35-3.42 (m, 1 H), 4.16 (dd, 1 H, J ) 13.2, 7.5
Hz), 6.05 (s, 1 H). 13C NMR: δ 206.9, 176.7, 165.1, 130.2, 47.6,
45.6, 45.5, 39.7, 39.1, 37.8. IR (CHCl3): ν 1740, 1710, 1620.
Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90.
Found: C, 67.91; H, 6.54; N, 7.73.
Tr icyclic 2-Azetid in on e 17c. Meth od A. From 0.06 g
(0.2 mmol) of a mixture of both diastereomers of 5b (74/26), a
crude reaction mixture containing both tricyclic â-lactams 17c
(77/23) was obtained as a white solid after filtration through
a short path of Celite. Combined yield: 95%. The major
diastereomer was separated as pure compound by chromatog-
raphy (2/1 EtOAc/hexane) in a 30% yield.
Tr icyclic 2-Azetid in on e, 19a . Meth od A. From 0.10 g
(0.3 mmol) of compound 6b-M, a crude reaction mixture
containing both diastereomers of compound 19a (70/30) was
obtained. From this mixture, 0.03 g (26%) of inseparable
diastereomers 19a was obtained as pale yellow oil after
purification by flash chromatography (1/2 EtOAc/hexane), and
0.05 g (51%) of starting material was recovered unchanged.
Ma jor Isom er . 1H NMR: δ 0.23 (s, 9 H), 1.74 (ddd, 1 H, J
) 13.8, 13.5, 5.4 Hz), 2.09 (dd, 1 H, J ) 18.3, 3.4 Hz), 2.44-
2.57 (m, 1 H), 2.65 (dd, 1 H, J ) 18.3, 6.6 Hz), 3.03-3.12 (m,
1 H), 3.68 (td, 1 H, J ) 5.4, 2.0 Hz), 3.80 (s, 3 H), 4.37 (dd, 1
H, J ) 5.4, 1.2 Hz), 5.14 (s broad, 1 H), 6.89-6.92 (d, 2 H),
7.35-7.38 (d, 2 H). 13C NMR: δ 210, 184.9, 166.6, 156.5, 144.5,
130.1, 118.4, 114.7, 62.9, 55.5, 55.0, 47.7, 42.2, 36.8, 26.4, -0.9.
Min or Isom er . 1H NMR: δ -0.1 (s, 9 H), 1.98 (dt, 1 H,
J ) 14.7, 5.1 Hz), 2.26 (dd, 1 H, J ) 18.4, 3.7 Hz), 2.54-2.57
(m, 1 H), 2.50 (dd, 1 H, J ) 18.4, 7.1 Hz), 3.23-3.28 (m, 1 H),
3.55 (ddd, 1 H, J ) 8.4, 5.4, 3.7 Hz), 3.79 (s, 3 H), 4.47 (dd, 1
H, J ) 5.4, 2.4 Hz), 5.33 (d, 1 H, J ) 2.4 Hz), 6.86-6.92 (d, 2
H), 7.30-7.38 (d, 2 H). 13C NMR: δ 205, 182.6, 166.1, 156.4,
144.5, 130.0, 118.3, 114.6, 64.9, 56.4, 55.0, 45.8, 45.2, 35.6, 25.3,
-1.0. IR (CHCl3): ν 3400 (broad), 1745, 1710, 1595. Anal.
Calcd for C20H25NO4Si: C, 64.66; H, 6.78; N, 3.77. Found: C,
64.95; H, 6.49; N, 3.98.
Tr icyclic 2-Azetid in on e, 19b. Meth od A. From 0.10 g
(0.4 mmol) of compound 6d -M, a crude reaction mixture
containing both tricyclic â-lactams 19b (70/30) was obtained.
From this mixture, both diastereomers of 2-azetidinone 19b
were obtained as pale yellow oils after purification by flash
chromatography (2/1 EtOAc/hexane). Combined yield: 0.06
g (55%).
Ma jor Isom er . Yellow oil: yield 0.03 g (30%). 1H NMR:
δ 1.42 (td, 1 H, J ) 13.7, 7.2 Hz), 1.63 (s broad, 1 H), 2.07 (dd,
1 H, J ) 18.9, 1.4 Hz), 2.57 (ddd, 1 H, J ) 12.5, 5.1, 1.5 Hz),
2.62 (dd, 1 H, J ) 18.9, 7.0 Hz), 2.89-2.97 (m, 1 H), 3.64 (t, 1
H, J ) 5.6 Hz), 3.73 (s, 3 H), 4.25 (dd, 1 H, J ) 5.6, 1.3 Hz),
4.82 (s broad, 1 H), 6.16 (s, 1 H), 6.82-6.87 (d, 2 H), 7.30-
7.41 (d, 2 H). IR (CHCl3): ν 3400 (broad), 1745, 1710, 1625,
1515. 13C NMR: δ 207.1, 174.9, 164.9, 156.7, 130.0, 129.5,
123.7, 116.1, 82.9, 66.1, 57.2, 45.7, 39.7, 34.5.
Min or Isom er . Yellow oil: yield 0.01 g (10%). 1H NMR:
δ 1.83-1.90 (m, 1 H), 2.16 (dd, 1 H, J ) 18.2, 2.9 Hz), 2.28-
2.19 (m, 1 H), 2.64 (dd, 1 H, J ) 18.2, 6.6 Hz), 2.82-2.89 (m,
1 H), 3.21 (d, 1 H, J ) 14.3 Hz), 3.46-3.53 (m, 1 H), 3.73 (s,
3 H), 3.81-3.90 (m, 1 H), 4.47 (td, 1 H, J ) 5.8, 2.5 Hz), 5.78
(s, 1 H), 6.86-6.92 (d, 2 H), 7.30-7.38 (d, 2 H). 13C NMR: δ
205.6, 179.2, 164.1, 157.0, 129.8, 128.9, 122.9, 115.6, 81.5, 67.0,
60.3, 44.5, 39.9, 39.0. IR (CHCl3): ν 3400 (broad), 1750, 1715,
1630. Anal. Calcd for C17H17NO4: C, 68.22; H, 5.72; N, 4.68.
Found: C, 67.95; H, 5.89; N, 4.99.
Gen er a l P r oced u r e for th e Syn th esis of Azetid in es 20.
To a suspension of LiAlH4 (3 mmol) in anhydrous Et2O (5 mL)
was added via cannula a solution of AlCl3 (3 mmol) in Et2O (5
mL) under argon pressure, and the mixture was refluxed for
30 min. The resulting AlH2Cl suspension was added dropwise
to a solution of corresponding azetidinone (1 mmol) dissolved
in Et2O (5 mL). The reaction was refluxed until complete
transformation of the starting material (TLC, ca. 15 min).
Then, the mixture was allowed to reach room temperature,
quenched with water (5 mL), and diluted with Et2O. The
organic layer was successively washed with water and brine
and dried (MgSO4). After filtration and evaporation of the
solvent under reduced pressure, the crude was purified by
flash chromatography. Spectroscopic and analytical data for
some representative forms of 20 follow.43
Ma jor Isom er . 1H NMR: δ 1.97 (dd, 1 H, J ) 19.0, 1.4
Hz), 2.49-2.58 (m, 2 H), 3.49-3.57 (m, 1 H), 3.60 (s, 1 H),
3.70 (dd, 1 H, J ) 4.4, 1.7 Hz), 4.37 (dd, 1 H, J ) 13.1, 7.8
Hz), 5.13 (d, 1 H, J ) 1.7 Hz), 5.34 (dd, 1 H, J ) 4.5, 1.6 Hz),
6.14 (s, 1 H), 6.99-7.11 (m, 3 H), 7.24-7.33 (m, 2 H). 13C
NMR: δ 207.0, 174.7, 164.8, 156.6, 130.1, 129.6, 123.8, 116.1,
83.0, 66.2, 57.2, 45.8, 39.0, 34.5. IR (KBr): ν 3540 (broad),
1770, 1715, 1645, 1600. Anal. Calcd for C16H15NO4: C, 67.36;
H, 5.30; N, 4.91. Found: C, 67.69; H, 5.08; N, 5.16.
Min or Isom er . 1H NMR: δ 2.05 (dd, 1 H, J ) 18.9, 2.1
Hz), 2.41-2.58 (m, 2 H), 3.48-3.54 (m, 1 H), 3.68 (s, 1 H),
3.69-3.72 (m, 1 H), 4.21 (dd, 1 H, J ) 12.9, 7.2 Hz), 4.71 (d,
1 H, J ) 7.8 Hz), 5.37 (dd, 1 H, J ) 3.8, 1.1 Hz), 6.28 (s, 1 H),
6.97-7.11 (m, 3 H), 7.24-7.33 (m, 2 H). 13C NMR: δ 205.6,
179.1, 164.1, 157.0, 129.8, 128.9, 122.9, 115.6, 81.5, 67.0, 60.2,
44.5, 39.9, 39.0. IR (KBr): ν 3330 (broad), 1760, 1700, 1675,
1630.
Tr icyclic 2-Azetid in on e, 18a . Meth od A. From 0.11 g
(0.3 mmol) of compound 6a -M, 0.04 g (32%) of tricyclic
compound 18a was obtained as a white solid and 0.07 g (64%)
of starting material 6a -M was recovered unchanged. Mp:
159-160 °C. 1H NMR: δ 0.05 (s, 9 H), 2.56 (dd, 1 H, J )
18.6, 6.9 Hz), 2.74 (dd, 1 H, J ) 18.6, 3.7 Hz), 2.86 (s broad, 1
H), 3.42-3.50 (m, 1 H), 3.75 (s, 3 H), 3.78 (dd, 1 H, J ) 9.3,
3.7 Hz), 4.43 (d, 1 H, J ) 3.7 Hz), 4.93 (d, 1 H, J ) 1.5 Hz),
6.76-6.79 (d, 2 H), 7.17-7.20 (d, 2 H). 13C NMR: δ 214.0,
186.2, 162.9, 156.4, 144.4, 129.8, 118.0, 114.4, 66.3, 61.8, 55.4,
52.9, 41.5, 38.9, -1.4. IR (KBr): ν 3350 (broad), 1745, 1680,
1630. Anal. Calcd for C19H23NO4Si: C, 63.84; H, 6.49; N, 3.92.
Found: C, 64.09; H, 6.61; N, 3.70.
cis-3-(Ben zyloxy)-2-et h yn yl-N-(2-p r op en yl)a zet id in e,
20a . From 0.30 g (1.2 mmol) of â-lactam 2, 0.24 g (86%) of
azetidine 20a was obtained as a colorless oil after purification
by flash chromatography (6/1 hexane/AcOEt). 1H NMR: δ 2.61
(d, 1 H, J ) 2.1 Hz), 3.15-3.22 (m, 3 H), 3.40 (td, 1 H, J ) 6.3,
1.2 Hz), 4.24-4.31 (m, 2 H), 4.42 (d, 1 H, J ) 11.7 Hz), 4.65
(d, 1 H, J ) 11.7 Hz), 5.09 (d broad, 1 H, J ) 10.2 Hz), 5.17 (d
broad, 1 H, J ) 19.2 Hz), 5.70-5.82 (m 1 H), 7.20-7.38 (m, 5
H). 13C NMR: δ 137.3, 134.2, 128.2, 128.0, 127.8, 117.3, 77.9,
77.8, 71.3, 69.2, 59.8, 59.3, 56.6. IR (CHCl3): ν 3310, 3100,

6796 J . Org. Chem., Vol. 63, No. 20, 1998
Alcaide et al.
2940, 2885, 1730. Anal. Calcd for C15H17NO: C, 79.26; H,
7.54; N, 6.16. Found: C, 79.48; H, 7.39; N, 6.07.
EtOAc/Et3N). Mp: ) 116-118 °C. [R]D ) -94.4 (c ) 1.0,
CHCl3) 1H NMR: δ 1.90 (dd, 1 H, J ) 1.17.6, 3.9 Hz), 2.26
(dd, 1 H, J ) 17.6, 6.4 Hz), 3.34-3.43 (m, 2 H), 3.68-3.73 (m,
1 H), 4.21 (dd, 1 H, J ) 8.8, 7.0 Hz), 4.96 (dd, 1 H, J ) 11.8,
6.3 Hz), 5.97 (s, 1 H), 6.71 (d, 2 H, J ) 8.1 Hz), 6.91 (t, 2 H, J
) 7.4 Hz), 7.17-7.24 (m, 3 H). 13C NMR: δ 209.5, 186.8, 156.4,
129.7, 125.9, 121.7, 114.7, 74.7, 66.6, 64.6, 56.4, 43.3, 41.6. IR
(CHCl3): ν 3010, 1715, 1610. Anal. Calcd for C15H15NO2: C,
74.67; H, 6.27; N, 5.80. Found: C, 74.30; H, 6.55; N, 5.63.
Tr icyclic Azetid in e 23. Meth od A. From 0.18 g (0.7
mmol) of compound 20d was obtained 0.20 g (95%) of a mixture
of both diastereomers 23 (75/25).
(+)-(2S ,3S )-3-P h e n oxy-N -(2-p r op yn yl)-2-vin yla ze t i-
d in e, (+)-20b. From 0.45 g (2.0 mmol) of â-lactam, (+)-3d
0.38 g (89%) of azetidine (+)-20b was obtained as a colorless
oil after purification by flash chromatography (6/1 hexane/
AcOEt). [R]D ) +107.8 (c ) 1.0). 1H NMR: δ 2.21 (t, 1 H, J
) 2.4 Hz), 3.31-3.37 (m, 3 H), 3.58 (dd, 1 H, J ) 8.7, 5.4 Hz),
4.07 (t broad, 1 H, J ) 6.9 Hz), 4.76 (td, 1 H, J ) 5.8, 1.6 Hz),
5.12 (dd, 1 H, J ) 9.9, 1.8 Hz), 5.25 (dd , 1 H, J ) 17.4, 1.8
Hz), 5.92-6.04 (m, 1 H), 6.71-6.75 (d, 2 H), 6.84-6.88 (t, 1
H), 7.14-7.20 (m, 2 H). 13C NMR: δ 157.6, 133.5, 129.3, 120.9,
119.2, 115.0, 78.1, 73.3, 71.4, 68.5, 54.7, 41.7. IR (CHCl3): ν
3310, 3020, 2970, 2860, 2410, 1715, 1605, 1595. Anal. Calcd
for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C, 79.18;
H, 7.39; N, 6.27.
Gen er a l Syn th esis of Tr icyclic Azetid in es 21-23, a n d
th e Azep in e 24. The experimental procedures were identical
to those used for the synthesis of tricyclic 2-azetidinones.
Rea ction of com p ou n d 20a . Meth od A. From 0.09 g (0.4
mmol) of compound 20a was obtained a crude containing a
mixture of compounds 24 and 21 (66/33). From this mixture
0.04 g (47%) of compound 24 was obtained by chromatography
(13/1 AcOEt/Et3N), and 0.05 g (42%) of a mixture containing
compound 21 and azepine 24.
Ma jor Isom er . 1H NMR: δ 2.19 (dd, 1 H, J ) 17.1, 3.9
Hz), 2.46 (dd, 1 H, J ) 17.1, 6.3 Hz), 2.68-2.89 (m, 2 H), 2.98-
3.02 (m, 1 H), 3.26-3.59 (m, 1 H), 3.42 (dd, 1 H, J ) 7.2, 2.7
Hz), 3.67 (s, 3 H), 3.769 (t, 1 H, J ) 7.8 Hz), 4.36 (t, 1 H, J )
5.4-6.0 Hz), 6.06 (s broad, 1 H), 6.217 (d, 2 H), 6.72 (d, 2 H).
13C NMR: δ 211.6, 186.8, 152.1, 145.8, 127.3, 114.7, 111.9,
67.6, 57.7, 55.8, 49.9, 38.1, 35.5, 33.4.
Min or Isom er . 1H NMR: δ 2.26 (dd, 1 H, J ) 17.4, 3.9
Hz), 2.65 (dd, 1 H, J ) 17.4, 6.3 Hz), 2.68-2.89 (m, 2 H), 2.92
(t, 1 H, J ) 8.6 Hz), 3.18-3.25 (m, 1 H), 3.62 (dd, 1 H, J ) 7.1,
4.6 Hz), 3.69 (s, 3 H), 3.98 (t, 1 H, J ) 7.4 Hz), 4.07 (dd, 1 H,
J ) 7.8, 4.5 Hz), 5.81 (t broad, 1 H, J ) 1.8 Hz), 6.28 (d, 2 H),
6.75 (d, 2 H). 13C NMR: δ 209.9, 188.6, 152.0, 143.6, 125.3,
114.9, 112.8, 71.4, 57.4, 55.8, 50.0, 42.3, 36.1, 33.7. IR
(CHCl3): ν 1710, 1640, 1510. Anal. Calcd for C16H17NO2: C,
75.27; H, 6.71; N, 5.49. Found: C, 75.61; H, 6.55; N, 5.73.
Azep in e 24. 1H NMR: δ 1.93 (dd, 1 H, J ) 18.4, 2.9 Hz),
2.48 (dd, 1 H, J ) 9.9, 8.1 Hz), 2.53 (dd, 1 H, J ) 13.3, 6.3
Hz), 2.76 (dd, 1 H, J ) 14.3, 2.6 Hz), 2.90-2.93 (m, 2 H), 3.14
(m, 1 H), 3.09-3.19 (m, 2 H), 3.51-3.58 (m, 1 H), 4.48 (dAB, 1
H, J ) 11.8 Hz), 4.54 (dAB, 1 H, J ) 11.8 Hz), 5.87 (d, 1 H, J
) 1.5 Hz), 7.08-7.5 (m, 5 H). 13C NMR: δ 208.3, 181.4, 138.2,
131.6, 128.5, 127.8, 127.6, 76.0, 70.9, 54.1, 53.9, 47.7, 41.4, 36.4.
IR (CHCl3): ν. Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44;
N, 5.44. Found: C, 74.95; H, 7.22; N, 5.71.
Ack n ow led gm en t. Support for this work under
Grant PB96-0565 (DGES, Spain) is acknowledged. C.P.
thanks the UCM for a predoctoral grant. We thank Prof.
Mar G. Gallego for a careful editing of the manuscript.
Tr icyclic Azetid in e 21a . 1H NMR: δ 2.10 (ddd, 1 H, J )
17.5, 3.0, 0.8 Hz), 2.44 (t, 1 H, J ) 12.0 Hz), 2.73 (dd, 1 H, J
) 17.5, 6.6 Hz), 3.10 (dd, 1 H, J ) 12.0, 7.5 Hz), 3.11-3.40
(m, 1 H), 3.68-3.82 (m, 1 H), 4.02 (dd, 1 H, 9.6, 6.6 Hz), 4.38
(d, 1 H, J ) 11.7 Hz), 4.46 (d, 1 H, J ) 11.7 Hz), 4.75 (d, 1 H,
J ) 6.6 Hz), 6.09 (d, 1 H, J ) 2.4 Hz), 7.20-7.30 (m, 5 H). 13C
NMR: δ 209.8, 184.9, 137.0, 128.5, 128.4, 128.0, 127.8, 71.6,
69.2, 68.9, 60.2, 59.2, 43.4, 40.9.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for compounds 1b, 8a ,b, 10a -d , 11b-d , 14a ,c,
5b, 6c,d , and 20c-d , as well as procedures for the isolation
of reduced 2-azetidinones and an example of characterization
of the cobalt complex derived from 2-azetidinone 1a (7 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Tr icyclic Azetid in e (-)-22. Meth od A. From 0.23 g (1.0
mmol) of compound (+)-20b, 0.16 g (66%) of (-)-22 was
obtained as a colorless solid after flash chromatography (10/1
J O980114H