Base-promoted isomerization of cis-4-formyl-2-azetidinones: Chemoselective C4-epimerization vs rearrangement to cyclic enaminones

Article abstract of DOI:10.1021/jo991984h

Two simple, efficient, and complementary methods for the regiospecific C4-epimerization of cis-4-formyl-2-azetidinones 1-3 are described. The first method uses 40% aqueous dimethylamine as reagent in heterogeneous medium with benzene at room temperature, in the presence of benzyltributylammonium bromide (3-4 mol %) as the phase-transfer catalyst. This transformation tolerates alkyl, alkenyl, alkynyl, aryl, and alkoxy substituents at the C3 of the 2-azetidinone ring. However, limitations of this isomerization are as follows: (i) only N-(p-methoxyphenyl)-β-lactams can be used, and (ii) transformation is less compatible with heteroatomic substituents bonded to the C3 position of the 2-azetidinone ring. A highly general solution to these problems relies on the use of sodium carbonate as the isomerization reagent in different solvents. We also describe a novel base-promoted rearrangement of the β-lactam ring to cyclic enaminones 6 and 21, involving an E1cB-elimination reaction in cis-4-formyl-2-azetidinones.

Full text of DOI:10.1021/jo991984h

J . Org. Chem. 2000, 65, 3453-3459
3453
Ba se-P r om oted Isom er iza tion of cis-4-F or m yl-2-a zetid in on es:
Ch em oselective C4-Ep im er iza tion vs Rea r r a n gem en t to Cyclic
En a m in on es
Benito Alcaide,* Moustafa F. Aly,1 Carolina Rodr´ıguez, and Alberto Rodr´ıguez-Vicente
Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad Complutense,
28040-Madrid, Spain
Received December 28, 1999
Two simple, efficient, and complementary methods for the regiospecific C4-epimerization of cis-4-
formyl-2-azetidinones 1-3 are described. The first method uses 40% aqueous dimethylamine as
reagent in heterogeneous medium with benzene at room temperature, in the presence of
benzyltributylammonium bromide (3-4 mol %) as the phase-transfer catalyst. This transformation
tolerates alkyl, alkenyl, alkynyl, aryl, and alkoxy substituents at the C3 of the 2-azetidinone ring.
However, limitations of this isomerization are as follows: (i) only N-(p-methoxyphenyl)-â-lactams
can be used, and (ii) transformation is less compatible with heteroatomic substituents bonded to
the C3 position of the 2-azetidinone ring. A highly general solution to these problems relies on the
use of sodium carbonate as the isomerization reagent in different solvents. We also describe a novel
base-promoted rearrangement of the â-lactam ring to cyclic enaminones 6 and 21, involving an
E1cB-elimination reaction in cis-4-formyl-2-azetidinones.
In tr od u ction
methoxyphenyl)-1,4-diazabuta-1,3-diene wherein the later
serves as a synthon of the corresponding R-formylimine.6
Consequently, the development of stereocontrolled meth-
ods for the synthesis of trans-4-formyl-â-lactams becomes
of great interest in â-lactam chemistry. In connection
with our investigations on the synthesis and synthetic
applications of chiral, functionalized 2-azetidinones,7 we
also required a facile access to these compounds. We
found that typical reagents used for epimerization on
related systems4f,8 failed to give the expected trans
isomers. Instead, complex mixtures of products were
4-Formyl-2-azetidinones are versatile building blocks
that can serve not only for the synthesis of â-lactam
antibiotics, including monobactams, carbapenems, car-
bacephems, and isooxacephems,2 but also for the prepa-
ration of other useful non-â-lactam synthetic targets such
as â-substituted aspartic acid derivatives and isoserines.3
Among the different methods for the synthesis of this
particular type of monocyclic â-lactams, the Staudinger
reaction on appropriately functionalized imines is prob-
ably the most used approach.4,5 However, regarding the
stereochemical outcome of the reported routes, a very
strong preference for cis-â-lactam formation is observed.
Work from our group has resulted in a general, totally
stereoselective one-pot synthesis of cis-4-formyl-â-lactams
based on the reaction of acid chlorides and 1,4-bis(4-
(4) See, for example: (a) Niu, Ch.; Miller, M. J . Tetrahedron Lett.
1995, 36, 497. (b) J arayaman, M.; Deshmukh, A. R.-A. S.; Bhawal, B.
M. J . Org. Chem. 1994, 59, 5921. (c) Palomo, C.; Cossio, F. P.; Cuevas,
C.; Lecea, B.; Mielgo, A.; Roman, P.; Luque, A.; Mart´ınez-Ripoll, M. J .
Am. Chem. Soc. 1992, 114, 9360. (d) Palomo, C.; Ontoria, J . M.;
Odriozola, J . M.; Aizpurua, J . M.; Gamboa, I. Chem. Commun. 1990,
503. (e) Thomas, R. C. Tetrahedron Lett. 1989, 30, 5239. (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. (g) Evans, D. A.; Williams, J . M. Tetrahedron Lett. 1988, 29,
5065. (h) Evans, D. A.; Sjo¨gren, E. B. Tetrahedron Lett. 1985, 26, 3783.
(5) (a) Palomo, C.; Aizpurua, J . M.; Gamboa, I.; Oiarbide, M. Eur.
J . Org. Chem. 1999, 3223, 3. (b) Georg, G. I.; Ravikumar, V. T. In The
Organic Chemistry of â-Lactams; Georg, G. I., Ed.; VCH Publishers,
Inc.: New York, 1993; Chapter 6, p 295.
(6) (a) Alcaide, B.; Mart´ın-Cantalejo, Y.; Plumet, J .; Rodr´ıguez-
Lo´pez, J .; Sierra, M. A. Tetrahedron Lett. 1991, 32, 803. (b) 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.
(7) See, for instance: (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.
Chem. Commun. 1999, 1913. (b) Alcaide, B.; Rodr´ıguez-Campos, I. M.;
Rodr´ıguez-Lo´pez, J .; Rodr´ıguez-Vicente, A. J . Org. Chem. 1999, 64,
5377. (c) Alcaide, B.; Alonso, J . M.; Aly, M. F.; Sa´ez, E.; Mart´ınez-
Alca´zar, M. P.; Herna´ndez-Cano, F. Tetrahedron Lett. 1999, 40, 5391.
(d) Alcaide, B.; Polanco, C.; Sierra, M. A. J . Org. Chem. 1998, 63, 6786.
(e) Alcaide, B.; Rodr´ıguez-Vicente, A.; Sierra, M. A. Tetrahedron Lett.
1998, 39, 163. (f) Alcaide, B.; Aly, M. F.; Sierra, M. A. J . Org. Chem.
1996, 61, 8819. (g) Alcaide, B.; Mart´ın-Cantalejo, Y.; Sierra, M. A. J .
Org. Chem. 1996, 61, 9156.
(1) Permanent address: Department of Chemistry, Faculty of
Science at Qena, South Valley University, Qena, Egypt.
(2) Selected examples: (a) Thomas, R. C. In Recent Progress in the
Chemical Synthesis of Antibiotics; Springer-Verlag: Berlin-Heidel-
berg, 1990; p 533. (b) Georg, G. I. In Studies in Natural Products
Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1989; Vol. 4,
p 431. (c) Bodurow, Ch.; Carr, M. A. Tetrahedron Lett. 1989, 30, 4081.
(d) Georg, G. I.; Kant, J . J . Org. Chem. 1988, 53, 692. (e) Mastalerz,
H.; Menard, M.; Vinet, V.; Desiderio, 3.; Fung-Tomc, T.; Kessler, R.;
Tsai, Y. J . Med. Chem. 1988, 31, 1190. (f) Mastalerz, H.; Vinet, H.
Chem. Commun. 1987, 1283. (g) Cainelli, G.; Panunzio; M., Basile, T.;
Bargini, A.; Giacomini, D. J . Chem. Soc., Perkin Trans. 1 1987, 2637.
(h) Georg, G. I.; Kant, J .; Gill, H. S. J . Am. Chem. Soc. 1987, 19, 1129.
(i) Hart, D. J .; Ha, D.-Ch. Tetrahedron Lett. 1985, 26, 5493.
(3) For an excellent review on the synthesis of â-amino acids and
their derivatives from â-lactams, see: (a) Palomo, C.; Aizpurua, J . M.;
Gamboa, I. in Enantioselective Synthesis of â-Amino Acids; J uaristi,
E., Ed.; Wiley-VCH: New York, 1997; Chapter 14, p 279. Selected
examples: (b) Duhamel, P.; Goument, B.; Plaquevent, J . Ch. Tetra-
hedron Lett. 1987, 28, 2595. (c) Broady, S. D.; Rexhausen, J . E.;
Thomas, E. J . Chem. Commun. 1991, 708. (d) Bose, A. K.; Womelsdorf,
J . F.; Krishnan, L.; Urbanczyk-Lipkowska, Z.; Shelly, D. C.; Manhas,
M. Tetrahedron 1991, 47, 5379. (e) Robinson, R. P.; Donahue, K. M. J .
Org. Chem. 1992, 57, 7309. (f) Palomo, C.; Cabre, F.; Ontoria, J . M.
Tetrahedron Lett. 1992, 33, 4819. (g) Annunziata, R.; Benaglia, M.;
Cinquini, M.; Cozzi, F.; Ponzini, F. J . Org. Chem. 1993, 58, 4746. (h)
Kende, A. S.; Koch, K.; Dorey, G.; Kaldor, I.; Liu, K. J . Am. Chem.
Soc. 1993, 115, 9842. (i) Palomo, C.; Aizpurua, J . M.; Gamboa, I.;
Maneiro, E.; Odriozola, B. Chem. Commun. 1994, 1505.
(8) Epimerization at C3 and/or C4 is effected by: (a) DBN: Bose, A.
K.; Narayanan, C. S.; Manhas, M. S. J . Chem. Soc., Chem. Commun.
1970, 975. (b) DBU: Hart, D. J .; Ha, D.-Ch. Tetrahedron Lett. 1985,
26, 5493. (c) Me3SiOTf: Chiba, T.; Nakai, T. Tetrahedron Lett. 1985,
26, 4647. (d) NaOH and n-BuLi: Alcaide, B.; Dom´ınguez, G.; Escobar,
G.; Parren˜o, U.; Plumet, J . Heterocycles 1986, 24, 1579. (e) Kawabata,
T.; Itoh, K.; Hiyam, T. Tetrahedron Lett. 1989, 30, 4837.
10.1021/jo991984h CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/09/2000

3454 J . Org. Chem., Vol. 65, No. 11, 2000
Alcaide et al.
Ta ble 1. Syn th esis of tr a n s-4-F or m yl-â-la cta m s 4
Ch a r t 1
reaction time
(h)
trans/cis yieldf
substratea,b
R1
Ac
Bd
product
ratioe
(%)
1a
1b
1c
1d
1e
1f
Et
allyl
propargyl
i-Pr
t-Bu
65
36
36
21
3
168
72
72
24
6
4a
4b
4c
4d
4e
4f
95:5
95:5
95:5
100:0
100:0
100:0
100:0
83
80
82
87
90
85
7a
Ph
BnO
15
16
24
16
1g
4g
obtained in all cases. This is probably due to the high
instability of the compound to the usual isomerization
conditions. We report here two simple, efficient, and
complementary methods for the synthesis of trans-4-
formyl-â-lactams through chemoselective C4-epimeriza-
tion of the corresponding cis isomers using both aqueous
solution of dimethylamine in heterogeneous phase and
sodium carbonate as isomerization reagents. On the other
hand, enaminones are valuable synthetic intermediates
for the construction of biologically active nitrogen het-
erocycles through aza-annulation reactions with acrylate
derivatives.9 In this context, we also describe a novel
base-catalyzed rearrangement of the â-lactam ring to
cyclic enaminones related to tetronic acid,10 involving an
E1cB-elimination reaction in cis-3-alkoxy-4-formyl-2-
azetidinones.
a
b
Starting substrates 1 were in all cases racemic. PMP )
4-methoxyphenyl. c Method A: reaction time in the presence of
d
benzyltributylammonium bromide. Method B: reaction time
without benzyltributylammonium bromide. e Determined from
integration in the 1H NMR (300 MHz) of the crude reaction
mixtures. f Yield of pure, isolated product with correct analytical
and spectral data.
mmol) in benzene (5 mL) containing benzyltributylam-
monium bromide (3-4 mol %), and the mixture was
stirred at room temperature. The reaction mixture was
subjected to an extractive workup to yield essentially
pure trans isomer 4, as shown in Table 1. This transfor-
mation tolerates alkyl, alkenyl, alkynyl, aryl, and alkoxy
substituents at the C3 of the 2-azetidinone ring. Com-
pounds 4a and 4d are of particular interest because they
are closely related to intermediates used in the synthesis
of PS-5 and PS-6 trans-carbapenem antibiotics.2a-b The
size of the C3 substituent on the 2-azetidinone influences
the conversion rate, sterically more demanding groups
decreasing the reaction time required for the isomeriza-
tion. However, compound 1h having a phenoxy group at
C3 fails to give the expected trans isomer; intractable
reaction mixtures with considerable loss of material were
obtained instead. cis-3-Phthalimido-â-lactam 1i also
failed to give the corresponding trans isomer. In this case,
reaction of dimethylamine with phthalimido group may
be responsible for this failure.12 However, two major
drawbacks in this isomerization are as follows: (i) only
N-(p-methoxyphenyl)-â-lactams can be used, and (ii)
transformation is not compatible with amino (and in
some cases oxygenated) substituents bonded to the C3
position of the 2-azetidinone ring.
Resu lts a n d Discu ssion
Racemic and enantiomerically pure cis-4-formyl-â-
lactams 1-3 were selected as starting materials since
they cover a representative variety of substituents with
different steric and electronic characteristics at positions
N1 and C3 of the â-lactam ring. All compounds 1-3
(Chart 1) were prepared using previously reported stan-
dard methodologies.6b,7f-gDue to the instability of the
â-lactam aldehydes to the previously reported reagents
and experimental conditions we thought in dimethyl-
amine, easily available as a 40% aqueous solution, as the
reagent of choice. After several experiments in various
solvents, we found the best results in benzene at room
temperature in heterogeneous medium. Furthermore, we
observed that the use of benzyltributylammonium bro-
mide as a phase-transfer catalyst notably shorthened
reaction times required for isomerization (compare meth-
ods A and B in Table 1).11 Thus, in a typical experiment,
a 40% aqueous solution of dimethylamine (1 mL) was
added to a solution of the cis-formyl-â-lactam 1 (0.4
The reaction course for this isomerization may be
rationalized according to two different pathways, involv-
ing either the enolate or the enamino-â-lactam as the
intermediates (Scheme 1). To confirm participation of
enamines 5 as intermediates in the isomerization process
we prepared compounds 5a ,b by reaction of cis-â-lactam
1d ,e with pyrrolidine13 in the presence of the ZnCl2/R-
phenylethylamine complex as catalyst, using benzene as
solvent and a Dean-Stark apparatus to remove the
water formed during the reaction.14 After 1 h in refluxing
(9) See, for example: (a) Paulvannan, K.; Stille, J . R. J . Org. Chem.
1994, 59, 1613. (b) Murphy, J . P.; Hadden, M.; Stevenson, P. J .
Tetrahedron 1997, 53, 11827. (c) Campos, P. J .; Arranz, J .; Rodriguez,
M. A. Tetrahedron Lett. 1997, 38, 8397. (d) Cave´, C.; LePorhiel-
Castellon, Y.; Daley, V.; Riche, C.; Chiaroni, A.; d’Angelo, J . Tetrahe-
dron Lett. 1997, 38, 8703. (e) Benovsky, P.; Stephenson, G. A.; Stille,
J . R. J . Am. Chem. Soc. 1998, 120, 2493. (f) Fustero, S.; de la Torre,
M. G.; J ofre, V.; Carlon, R. P.; Navarro, A.; Fuentes, A. S.; Carrio, J .
S. J . Org. Chem. 1998, 63, 8825. (g) Fustero, S.; de la Torre, M. G.;
Pina, B.; Fuentes, A. S. J . Org. Chem. 1999, 64, 5551.
(12) The use of methylamine as deprotecting phthalimido group has
been reported. See, for example: Motawia, M. S.; Wengel, J .; Abdel-
Megid, A. E.-S.; Pedersen, E. B. Synthesis 1989, 384.
(13) Due to the difficulties to obtain enamines from dimethylamine,
(10) For a general review on enaminones, see: Greenhill, J . V. Chem.
Rev. 1977, 6, 277.
(11) Similar rate acceleration was observed for other catalysts, such
as Bu4N+I-, Bu4N+HSO4-, BnEt3N+Cl-. Complexation of R4N+ with
the formyl oxygen could be responsible for this catalytic effect on the
isomerization.
we used pyrrolidine as
enamines.
(14) Reaction conditions typically used for the synthesis of imines
when either the amine or the carbonyl compound are less reactive.
See, for example: Alcaide, B.; Moreno, A. M.; Rodr´ıguez-Vicente;
Sierra, M. A. Tetrahedron: Asymmetry 1996, 7, 2203.
a model amine to prepare pure, isolable

Isomerization of cis-4-Formyl-2-azetidinones
J . Org. Chem., Vol. 65, No. 11, 2000 3455
Sch em e 1
Sch em e 3a
a
Key: (i) Na2CO3, acetonitrile-water (1:1); (ii) Ph3PdCHCO2Me,
Ta ble 2. Rea ction of cis-4-F or m yl-â-la cta m s 1 w ith
Et2O, ∆.
Na 2CO3 in Meth a n ola
1
1
for isomerization. Next, we investigated epimerization of
derivatives cis-1g,h having alkoxy substituents at posi-
tion C3. To our surprise, a clean transformation to cyclic
enaminone 6 was observed in both cases, instead of the
expected C4-epimerization (entries 5 and 6). Enantio-
merically pure 3-alkoxyderivative cis-2b, having an N-
benzyl group, behaves in similar way, although in this
case the product was unstable and quickly evolved to a
complex reaction mixture of unidentified products. When
compound cis-3a , having a nitrogenated substituent at
C3 was used, neither the corresponding trans-4-formyl
derivative nor the cyclic enaminone was obtained, and
as in the previous case a complex reaction was observed.
This new reaction, which involves a tandem E1cB-
elimination-rearrangement process of the intermediate
enolate, will be studied later in this paper.15
Due to participation of methanol in the above reactions,
we used other different solvents in order to prevent
rearrangement process and to get the desired C4-isomer-
ization in substrates having heteroatomic substituents
on C3. We found that a homogeneous mixture of sodium
carbonate in acetonitrile-water gave the best results
(Scheme 3, Table 3).16 Reaction times shown in Table 3
were the optimum for each compound. Longer reaction
times gave complex crude mixtures and lower yields.
Because of the considerable loss of yield during chro-
matographic purification, the crude trans/cis mixtures of
â-lactam aldehydes were transformed by Wittig olefina-
tion into the corresponding trans/cis mixtures of R,â-
unsaturated esters E-9 and E-10, stereoselectively.3a,17
In this way, good yields of compounds E-trans-9 and
E-trans-10 were obtained, better than that of the corre-
sponding trans-formyl-â-lactams 7 and 8, when these
compounds were isolated by chromatography (see, for
example, entries 1 and 5). It is important to note that
the small amount of cis isomers 9 and 10 arising from
unreactive minor cis stereoisomers 2 and 3 were easily
removed at this point by column chromatography.
reaction
time (h) product
trans/cis yielde
entry substrateb,c
R1
Et
i-Pr
t-Bu
Ph
ratiod
(%)
1
2
3
4
5
6
1a
1b
1c
1d
1g
1h
4
4
2
4
3
3
4a
4b
4c
4d
6
100:0
100:0
100:0
100:0
>95
>95
>95
>95
80f
BnO
PhO
6
80f
a
Compound 1 (1 mmol), Na2CO3 (2 mmol), and methanol (30
b
mL) were used. Starting substrates 1 were in all cases racemic.
d
c PMP ) 4-methoxyphenyl. Determined from integration in the
1H NMR (300 MHz) of the crude reaction mixtures. e >95%
conversion by 1H NMR observed in all cases (No further purifica-
tion needed). f Isolated yield after column chromatography.
benzene, compounds 5 were obtained as mixtures of E/ Z
isomers [(1:1) for 5a and (95:5) for 5b]. Crude enamines
were stirred with water in benzene at room temperature
to give trans/cis mixtures of the corresponding 4-formyl-
â-lactams [(75:25) for 5a and (95:5) for 5b, after 48 and
72 h, respectively] (Scheme 2). Although not conclusive
at all, these experiments suggest that enamines are not
the actual intermediates in the isomerization since their
hydrolysis requires longer reaction times for a lower cis/
trans stereoselectivity to be obtained.
Sch em e 2a
a
Key: (i) pyrrolidine, benzene, ZnCl2‚R-phenylethylamine com-
plex (cat.), ∆; (ii) water-benzene.
(15) Access to diverse structural types of natural or synthetic
compounds lacking the â-lactam ring have been reported by cleavage
of the 2-azetidinone ring through any of the four possibilities. See, for
example: (a) Manhas, M. S.; Wagle, D. R.; Chiang, J .; Bose, A. K.
Heterocycles 1988, 27, 1755. (b) Alcaide, B.; Mart´ın-Cantalejo, Y.;
Sierra, M. A. J . Org. Chem. 1996, 61, 9156 and references therein.
(16) Very recently, a related cis/trans isomerization of N-Boc-2,2-
dimethyloxazolidine-5-carbaldehydes using K2CO3 in methanol has
been reported. See: Pasto´, M.; Moyano, A.; Perica´s, M. A.; Riera, A.
Tetrahedron Lett. 1998, 39, 1233.
To overcome limitations of the above method, we used
sodium carbonate as isomerization reagent. First, we
tested isomerization of 3-alkyl and 3-arylderivatives 1a
and 1d -f using sodium carbonate in methanol at room
temperature, to check the utility of this reagent in
comparison with the previously used dimethylamine.
Essentially pure trans isomers 4 were obtained in almost
quantitative yields in all cases (Table 2, entries 1-4). As
shown in Table 2, better yields and stereoselectivities
were obtained, and shorter reactions times were required
(17) Wittig reaction involving 4-formyl-â-lactams is
a versatile
methodology frequently used for the synthesis of different functional-
ized â-amino acids. See, for example: (a) Palomo, C.; Arrieta, A.; Cossio,
F. P.; Aizpurua, J . M.; Mielgo, A.; Aurrekoetxea, N. Tetrahedron Lett.
1990, 31, 6429. See also refs 3i and 7b.

3456 J . Org. Chem., Vol. 65, No. 11, 2000
Alcaide et al.
Ta ble 3. Rea ction of cis-4-F or m yl-â-la cta m s 2 a n d 3 w ith Na 2CO3 in Aceton itr ile-Wa ter a a n d Su bsequ en t Wittig
Olefin a tion w ith P h 3P dCHCO2Me
yield (%)d
isomerization
time (h)
trans/cis
ratioc
entry
substrateb
R1
R2
PMP
Bn
allyl
propargyl
PMP
PMP
Bn
trans-7/8
E-trans-9/10
1
2
3
4
5
6
7
(+)-2a
(+)-2b
(+)-2c
(+)-2d
(+)-2e
(+)-3a
(+)-3b
Bn
Bn
Ph
Ph
Ph
-
16
48
24
24
3
85:15
85:15
80:20
75:25
80:20
95:5e
93:7
(-)-7a (60)
(+)-7b (45)
(+)-7c (60)
(-)-9a (85)
(+)-9b (60)
(+)-9d (50)
(-)-9e (65)
(+)-10a (67)
(+)-10b (70)
(-)-7e (55)
24
96
-
a
b
Substrate 1-3 (1 mmol), Na2CO3 (2 mmol), and acetonitrile-water (1/1, 30 mL) were used. Starting substrates 2 and 3 were used
as enantiopure cis isomers. c Determined from integration in the 1H NMR (300 MHz) of the crude reaction mixtures. Yields refer to
isolated products after column chromatography starting from the corresponding cis isomers. e Percentage (95%) of trans isomer 8a refers
to a mixture of both trans C4- and C3-epimers (80% and 15%, respectively).
d
Sch em e 4
Sch em e 5a
Chemoselective C4-epimerization was observed in all
cases except for compound cis-3a, in which minor C3-isom-
erization was also observed (see Table 3, footnote d).18
Finally, two sets of experiments were carried out in
order to demonstrate the C4-chemoselective epimeriza-
tion. First, isomerization of compound cis-1e by treat-
ment with Na2CO3 in deuterated methanol gave trans-
4-deutero derivative 11 in almost quantitative yield. Also,
treatment of compound cis-1h with Na2CO3 in CH3CN-
D2O yielded a trans/cis mixture (80/20) of deuterated
compounds, from which trans-4-deutero compound 12
was easily obtained (50% as pure product) after column
chromatography (Scheme 4). Compounds 11 and 12 were
unambiguosly identified by 1H and 13C NMR through
comparison with the corresponding spectra for trans
isomers 4e and 4h , respectively (see Figures 1 and 2 in
the Supporting Information).
In a second experiment, absolute configuration of
â-lactam aldehyde (-)-7b ([R]D ) -88, c 1.5 CHCl3)
[obtained through isomerization of (+)-cis-(3R,4R)-4-
formyl-â-lactam 2b following the above methods] was
determined by comparison with (+)-trans-(3S,4R)-4-
formyl-â-lactam, ent-7b, prepared from acetal â-lactam
(+)-16. Compound (+)-16 and its C3-epimer (+)-17 were
prepared through a well-established protocol reported by
Bose4f (Scheme 5). Reaction of compound (+)-17 with
sodium methoxide in methanol gave the corresponding
trans-3-hydroxy derivative (+)-18, which was trans-
formed into the (+)-trans-3-benzyloxy-2-azetidinone 19
by benzylation under phase-transfer conditions. Standard
acetonide hydrolysis, followed by cleavage of the resulting
diol (NaIO4/MeOH/H2O), yielded (3S,4S)-trans-4-formyl-
2-azetidinone ent-7b ([R]D ) +90, c 1.5 CHCl3). Com-
a
Key: (i) PTSA, THF/H2O (1:1), ∆; (ii) NaIO4, CH2Cl2/water
(100:1), rt; (iii) DMA or Na2CO3 isomerization; (iv) see ref 4f; (v)
NaOMe, MeOH, rt; (vi) BnBr, CH2Cl2/NaOH(50%), Bu3BnN+Br-.
pounds (-)-7b and ent-7b had identical physical and
spectroscopic properties except for optical rotations,
which were of the same value, but of opposite sign as
corresponds to enantiomers. Thus, the 3R,4R configura-
tion can be assigned to (-)-7b. Therefore, these results
clearly demonstrate that C4-epimerization was the only
stereochemical outcome of the base-promoted reactions
reported herein.
As we have previously stated, reaction of compounds
1g and 1h with Na2CO3 in methanol smoothly gave cyclic
enaminone 6. This compound is closely related to enami-
nones derived from tetronic acid, valuable synthetic
intermediates for the construction of biologically active
nitrogen heterocycles through aza-annulation reactions
with acrylate derivatives.10 To explore the scope of this
new reaction, we prepared a set of different substituted
2-azetidinones 20, having as structural requirement both
an acyl group at position 4 and at least one leaving group
on position 3 of the â-lactam ring. Compounds 20 were
obtained following previously reported methods (see the
Experimental Section). Thus, reaction of compounds 20
with Na2CO3 in methanol at room temperature for the
reaction times indicated in Table 4, smoothly gave the
corresponding substituted cyclic enaminones 21. Pure
(18) Partial epimerization at C3 in a 3-amino-substituted â-lactam
has been reported using a mixture of NaHCO3 and Na2CO3. See, for
instance: Palomo, C.; Aizpurua, J . M.; Legido, M.; Mielgo, A.; Galarza,
R. Chem. Eur. J . 1997, 3, 1432.

Isomerization of cis-4-Formyl-2-azetidinones
J . Org. Chem., Vol. 65, No. 11, 2000 3457
Sch em e 7a
Ta ble 4. Syn th esis of Cyclic En a m in on es 21
a
susbtratea R1
R2 R3
R4
PMP
PMP
PMP
t (h) product yieldb (%)
Key: (i) PhCH2COCl, Et3N, rt; (ii) Na2CO3, MeOH.
20a
20b
20c
20d
20e
20f
Br
Cl
Cl
BnO
PhO
PhO
Et
Me
Cl
H
H
H
H
3
3
3
21a
21b
21c
21d
21e
21f
85
76
80
32c
80
70
pound 26 were identical to those reported in the litera-
ture for the Z-isomer, obtained by an independent route.21
In this case, the final product is the enaminodiester 26
since this open compound (type 23) is unable to yield the
intermediate hemiacetal (type 24) and, hence, final
lactonization to the corresponding cyclic enaminone.
In conclusion, we have demonstrated that both aqueous
solution of dimethylamine in heterogeneous phase and
sodium carbonate in different solvents promote the
regiospecific C4-epimerization of cis-3-substituted 4-formyl-
2-azetidinones. The former is particularly effective for
N-(p-methoxyphenyl)-2-azetidinones having alkyl or aryl
substituents at C3, while the latter is more general and
advangeous independently of the type of substituents at
positions N1 and C3 of the â-lactam ring. Hence, these
two methods complements each other and enable the
regiospecific C4-epimerization of a wide variety of cis-4-
formyl â-lactams. In addition, a novel base-promoted
rearrangement of the â-lactam ring to cyclic enaminones
related to tetronic acid, involving an E1cB-elimination
reaction in cis-3-alkoxy-4-formyl-2-azetidinones, has been
uncovered. We have also demonstrated the generality of
this process for other structurally related compounds
having acyl groups on C4 and a good leaving group on
C3 of the â-lactam ring. Studies concerning further
applications of these new processes are now in progress.
Me Propargyl 1.5
H
H
Me PMP
Ph PMP
6
48
a
b
Starting compounds 20 were in all cases racemic. Yields are
for pure products purified by column chromatography. c Consid-
erable loss of material was observed in this case after chromato-
graphic purification.
Sch em e 6
Exp er im en ta l Section
compounds 21 were isolated in good to excellent yields
(70-85%) by flash chromatography, but some decomposi-
tion was observed for the sensitive N-propargylenami-
none 21d during purification. The above results strongly
suggest that an acyl group able to stabilize a negative
charge at C4 position, and a good leaving group on C3,
are necessary for the process to occur. Formation of
compounds 21 may be rationalized through a tandem
E1cB-elimination-rearrangement process of the enolate
generated initially, followed by ring opening of the
resulting highly strained 2-azetinones 22,19,20 as shown
in Scheme 6. Further intramolecular transesterification
of the resulting hemiacetal enaminoester 23 gives final
enamine lactone 21. One of the reviewers has suggested
an alternative reaction pathway involving addition of
methanol to intermediate 22 and further lactonization
of the resulting hemiacetal 24 to give enaminone 21.
To achieve more information of the process, we used
as substrate the 3-phenoxy-4-methoxycarbonyl-â-lactam
25,4d with an ester group on C4 instead of the aldehyde
or ketone moieties present in related compounds 20.
Thus, treatment of compound 25 with Na2CO3 in metha-
nol at room temperature for 3 h gave enaminodiester 26,
along with phenol (Scheme 7). Spectral data for com-
Gen er a l Meth od s. General experimental data and proce-
dures have been previously reported.7b NMR spectra were
recorded in CDCl3 solutions, except 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 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 starting materials
were prepared according to reported procedures: cis-1-(p-
methoxyphenyl)-3-isopropyl-4-formyl-2-azetidinone,6b cis-1-(p-
methoxyphenyl)-4-formyl-3-phenyl-2-azetidinone,6b cis-1-(p-
methoxyphenyl)-4-formyl-3-phenoxy-2-azetidinone,6b cis-1-(p-
methoxyphenyl)-3-benzyloxy-4-formyl-2-azetidinone,6b cis-1-(p-
methoxyphenyl)-3-ethyl-4-formyl-2-azetidinone,6b
cis-1-(p-
methoxyphenyl)-3-bromo-3-ethyl-4-formyl-2-azetidinone,6b
cis-1-(p-methoxyphenyl)-3-chloro-4-formyl-3-methyl-2-azetidi-
none,6b cis-1-(p-methoxyphenyl)-3,3-dichloro-4-formyl-2-azetidi-
none,6b (+)-(3R,4S)-cis-1-(p-methoxyphenyl)-3-benzyloxy-4-
[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidinone,4f (+)-(3R,4S)-
cis-3-acetoxy-1-(p-methoxyphenyl)-4-[(S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]-2-azetidinone,4f (+)-(3R,4S)-cis-1-(p-methoxyphenyl)-
4-[(S )-2,2-dim et h yl-1,3-dioxola n -4-yl]-3-h ydr oxy-2-a zet i-
dinone,4f (+)-(3R,4S)-cis-1-(p-methoxyphenyl)-4-[(S)-2,2-di-
methyl-1,3-dioxolan-4-yl]-3-mesyloxy-2-azetidinone,4f (+)-(3S,4S)-
trans-3-acetoxy-1-(p-methoxyphenyl)-4-[(S)-2,2-dimethyl-1,3-
dioxolan-4-yl]-2-azetidinone,4f (+)-cis-(1-benzyl)-3-[(S)-4-phenyl-
2-oxooxazolidin-3-yl]-4-formyl-2-azetidinone,4h (+)-(3R,4S)-cis-
4-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-(2-propynyl)-3-phenoxy-
2-azetidinone,7b cis-3-benzyloxy-4-(R-methylstyryl)-1-(2-propyn-
(19) For a review on the chemistry of azetines, see: De Kimpe, N.
In Comprehensive Heterocyclic Chemistry II; Padwa, A., Ed.; Elsevier:
Oxford, 1996; Vol. 1, Chapter 1.18.4, p 575.
(20) The synthesis of 1-acyl-4-oxo-2-azetines has been reported. See,
for example: Arbuzov, B. A.; Zobova, N. N. Synthesis 1974, 461.
(21) (a) Huisgen, R.; Herbig, K.; Siegl, A.; Huber, H. Chem. Ber.
1966, 99, 2526. (b) Greenhill, J . V.; Ramli, M.; Tomassini, Th. J . Chem.
Soc., Perkin Trans. 1 1975, 588.

3458 J . Org. Chem., Vol. 65, No. 11, 2000
Alcaide et al.
yl)-2-azetidin-one,7b cis-3-allyl-1-(p-methoxyphenyl)-4-formyl-
2-azetidinone,7d cis-1-(p-methoxyphenyl)-4-formyl-3-(2-propynyl)-
2-azetidinone,7d (+)-(3R,4S)-cis-4-formyl-3-phenoxy-1-(2-pro-
penyl)-2-azetidinone,7d (+)-cis-(1-p-methoxyphenyl)-4-formyl-
3-[(S)-4-phenyl-2-oxooxazolidin-3-yl]-2-azetidinone,7g cis-1-(p-
methoxyphenyl)-3-phenoxy-4-benzoyl-2-azetidin-one,22 and meth-
yl glyoxalate hydrate.23
117.5, 114.5, 63.5, 59.7, 55.5, 31.5, 27.1. IR (KBr) ν: 1760,
1740. MS m/z: 261 (M+, 84), 232 (8), 204 (70), 149 (28), 134
(100). Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36.
Found: C, 69.74; H, 7.06; N, 5.12.
(-)-(3R ,4S )-t r a n s-3-Be n zyloxy-4-for m yl-1-(p -m e t h -
oxyp h en yl)-2-a zetid in on e (7a ). Following method B or C
starting from (+)-2a , as described for the above product (()-
4g. This compound was found to be identical with the one
described above on the basis of their spectral data. Yield: 60%
(either method). White solid. Mp: 146-148 °C (AcOEt/hexane).
[R]D ) -88 (c 1.5, CHCl3).
(+)-(3R,4S)-1-Ben zyl-3-b en zyloxy-4-for m yl-2-a zet id i-
n on e (7b). Meth od D. Reaction time: 48 h. From 0.10 g (0.34
mmol) of (+)-2b, 0.05 g (45%) of (+)-7b was obtained after
purification by flash chromatography (hexane/AcOEt 2/1).
Colorless oil. [R]D ) +44.9 (c 2, CHCl3). 1H NMR (CDCl3) δ:
3.85 (t, 1H, J ) 1.5 Hz), 4.21 (d, 1H, J ) 14.7 Hz), 4.58 (d, 1H,
J ) 11.8 Hz), 4.58 (d, 1H, J ) 1.5 Hz), 4.74 (d, 1H, J ) 14.7
Hz), 4.79 (d, 1H, J ) 11.8 Hz), 7.1-7.4 (m, 10H), 9.08 (d, 1H,
J ) 1.5 Hz). IR (CHCl3) ν: 1760. MS m/z: 296 (M+ + 1, 3),
163 (8), 133 (7), 91 (100). Anal. Calcd for C18H17NO3: C, 73.20;
H, 5.80; N, 4.74. Found: C,73.39; H, 5.99; N, 4.44.
(+)-(3R,4S)-1-Allyl-4-for m yl-3-p h en oxy-2-a zet id in on e
(7c). Meth od D. Reaction time: 3 h. From 0.10 g (0.43 mmol)
of (+)-2c, 0.06 g (60%) of (+)-7c was obtained after purification
by flash chromatography (hexane/AcOEt 2/1). Colorless oil. [R]D
) +29 (c 2, CHCl3). 1H NMR (CDCl3) δ: 3.81 (dd, 1H, J ) 7.2,
15.4 Hz), 4.12 (dd, 1H, J ) 5.7, 15.4 Hz), 4.23 (t, 1H, J ) 1.8
Hz), 5.18 (m, 3H), 5.81 (m, 1H), 6.96 (m, 3H), 7.20 (m, 2H),
9.81 (d, 1H, J ) 1.8 Hz). 13C NMR (CDCl3) δ: 196.7, 164.2,
156.9, 130.6, 130.0, 123.2, 120.7, 115.8, 82.2, 65.6, 44.7. IR
(CHCl3) ν: 1760. Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67;
N, 6.06. Found: C, 67.22; H, 5.43; N, 6.20.
Gen er a l P r oced u r e for th e Syn th esis of tr a n s-â-La c-
ta m s 4, 7, 9, 10, 11, a n d 12. Meth od A. A mixture of the
starting cis-â-lactam (1 mmol) and dimethylamine (40% aq, 1
mL) in benzene (10 mL) was stirred at room temperature until
complete disappearance of the starting material (TLC). The
organic layer was extracted, and the crude material was
purified by flash chromatography (silica gel, hexane/AcOEt
mixtures). Meth od B. A mixture of the starting cis-â-lactam
(1 mmol), benzyltributylammonium bromide (0.05 mmol), and
dimethylamine (40% aq, 1 mL) in benzene (10 mL) was stirred
at room temperature until complete disappearance of the
starting material (TLC).Then, the organic layer was extracted
and the crude material was purified by flash chromatography
(silica gel, hexane/AcOEt mixtures). Meth od C. A mixture of
the starting cis-â-lactam (1 mmol) and sodium carbonate (2
mmol) in methanol (10 mL) was stirred at room temperature
until complete disappearance of the starting material (TLC).
The mixture was concentrated, extracted with CH2Cl2, and
dried (MgSO4). After removal of the solvent, the desired
product was obtained without further purification. Meth od
D. A solution of the starting cis-â-lactam (1 mmol) and sodium
carbonate (2 mmol) in a mixture of acetonitrile/water (1:1, 30
mL) was stirred at room temperature. The organic layer was
extracted with AcOEt (×5) and dried (MgSO4), and the solvent
was removed under reduced pressure. The resulting crude
mixture was purified by flash chromatography (silica gel,
hexane/AcOEt mixtures). Meth od E. The crude product
obtained using method C (1 mmol of starting cis â-lactam) was
dissolved in ether (10 mL), and Ph3PdCHCO2Me (1.2 mmol)
was added. The mixture was stirred and heated at reflux until
complete disappearance of the starting material (TLC). After
removal of the solvent under reduced pressure, the product
was purified by column chromatography (silica gel, hexane/
AcOEt mixtures) to yield E isomer exclusively. Spectroscopic
and analytical data for some representative pure forms of
compounds 4, 7, 9, 10, 11, and 12 follow.24
(-)-(3R,4S)-4-F or m yl-1-(p-m eth oxyp h en yl)-3-p h en oxy-
2-a zetid in on e (7e). Meth od D. Reaction time: 3 h. From
0.20 g (0.67 mmol) of (+)-2e, 0.11 g (56%) of (-)-7e was
obtained after purification by flash chromatography (hexane/
AcOEt 2/1). Colorless oil. [R]D ) -30 (c 1, CHCl3). 1H NMR
(CDCl3) δ: 3.80 (s, 3H), 4.62 (dd, 1H, J ) 1.8, 3.3 Hz), 5.34 (d,
1H, J ) 1.8 Hz), 6.92 (d, 2H, J ) 7.0 Hz), 7.06 (m, 3H), 7.25-
7.4 (m, 4H), 9.93 (d, 3.3 Hz). 13C NMR (CDCl3) δ: 196.8, 160.8,
157.1, 156.6, 129.9, 123.1, 118.4, 115.6, 115.8, 114.6, 81.4, 65.6,
55.5. IR (CHCl3) ν: 1760. MS m/z: 297 (M+, 90), 241 (15), 176
(42). Anal. Calcd for C17H15NO4: C, 68.68; H, 5.08; N, 4.71.
Found: C, 68.87; H, 5.31; N, 4.86.
(()-tr a n s-4-F or m yl-3-isop r op yl-1-(p-m eth oxyp h en yl)-
2-a zetid in on e (4d ). Meth od A. Reaction time: 24 h. Meth od
B. Reaction time: 21 h. From 0.20 g (0.81 mmol) of (()-1d ,
0.17 g (87%) of (()-4d was obtained after purification by flash
chromatography (hexane/AcOEt 3/1). Colorless oil. (Meth od
C. Reaction time: 4 h, quantitative yield). 1H NMR (CDCl3)
δ: 0.98 (d, 3H, J ) 6.9 Hz), 1.07 (d, 3H, J ) 6.9 Hz), 2.05 (m,
1H), 3.05 (dd, 1H, J ) 2.7, 8.1 Hz), 3.75 (s, 3H), 4.08 (dd, 1H,
J ) 2.7, 4.2 Hz), 6.79 (d, 2H, J ) 6.9 Hz), 7.18 (d, 2H, J ) 6.9
Hz), 9.65 (d, 1H, J ) 4.2 Hz). 13C NMR (CDCl3) δ: 198.8, 167.7,
156.4, 131.1, 117.4, 114.4, 60.9, 59.4, 55.4, 27.9, 20.0, 19.8. IR
(CHCl3) ν: 1760, 1740. MS m/z: 247 (M+, 71), 218 (8), 190
(58), 149 (28), 134 (100). Anal. Calcd for C14H17NO3: C, 68.00;
H, 6.93; N, 5.66. Found: C, 68.24; H, 7.12; N, 5.60.
(-)-(3R,4R)-3-Ben zyloxy-4-(2-m eth oxycar bon yl)eth en yl-
1-(p-m eth oxyp h en yl)-2-a zetid in on e (9a ). Meth od E. From
(+)-2a (0.1 g, 0.32 mmol), 0.1 g (85%) of (-)-9a was obtained
1
as a colorless oil. [R]D ) -60 (c 2, CHCl3). H NMR (CDCl3) δ:
3.65 (s, 3H), 3.70 (s, 3H), 4.28 (dc, 1H, J ) 1.0, 1.7, 4.0, 7.1),
4.45 (d, 1H, J ) 1.7 Hz), 4.53 (d, 1H, J ) 11.7 Hz), 4.84 (d,
1H, J ) 11.7 Hz), 5.76 (dd, 1H, J ) 1.0, 15.9 Hz), 6.64 (dd,
1H, J ) 7.1, 15.9 Hz), 6.76 (d, 2H, J ) 9.0 Hz), 7.16 (d, 2H, J
) 9.0 Hz), 7.30 (s, 5H). 13C NMR (CDCl3) δ: 165.8, 162.7, 156.8,
142.4, 136.7, 130.5, 128.9, 128.8, 128.7, 128.5, 118.9, 114.7,
87.6, 72.7, 61.1, 55.6, 52.0. IR (KBr) ν: 1755, 1724, 1510. Anal.
Calcd for C21H21NO5: C, 68.65; H, 5.76; N, 3.81. Found: C,
68.43; H, 5.65; N, 4.02.
(()-tr a n s-3-ter t-Bu t yl-4-for m yl-1-(p -m et h oxyp h en yl)-
2-a zetid in on e (4e). Meth od A. Reaction time: 6 h. Meth od
B. Reaction time: 3 h. From 0.20 g (0.77 mmol) of (()-1e, 0.18
g (90%) of (()-4e was obtained after purification by flash
chromatography (hexane/AcOEt 3/1). White solid. Mp: 120-
122 °C (AcOEt/hexane). (Meth od C. Reaction time: 2 h,
(+)-(3R,4R)-1-Ben zyl-3-ben zyloxy-4-(2-m eth oxyca r bo-
n yl)eth en yl-2-a zetid in on e (9b). Meth od E. From 0.20 g
(0.68 mmol) of (+)-2b, 0.12 g (60%) of (+)-9b was obtained after
purification by flash chromatography (hexane/AcOEt 2/1).
Colorless oil. [R]D ) +7.5 (c 3, CHCl3). 1H NMR (CDCl3) δ: 3.74
(s, 3H), 3.82 (ddd, 1H, J ) 0.7, 1.5, 8.1 Hz), 3.95 (d, 1H, J )
15.0 Hz), 4.45 (d, 1H, J ) 1.5 Hz), 4.54 (d, 1H, J ) 11.6 Hz),
4.73 (d, 1H, J ) 15.0 Hz), 4.79 (d, 1H, J ) 11.6 Hz), 5.74 (dd,
1H, J ) 0.7, 15.8 Hz), 6.56 (dd, 1H, J ) 8.1, 15.8 Hz), 7.2-7.3
(m, 10H). 13C NMR (CDCl3) δ: 166.0, 165.6, 142.4, 136.4, 134.6,
128.9, 128.7, 128.6, 128.5, 128.5, 128.1, 124.1, 87.7, 73.2, 60.2,
51.9, 44.8. IR (CHCl3) ν: 1760, 1724. MS m/z: 352 (M+ + 1,
2), 218 (10), 91 (100). Anal. Calcd for C21H21NO4: C, 71.78; H,
6.02; N, 3.99. Found: C, 71.89; H, 5.87; N, 3.65.
1
quantitative yield). H NMR (CDCl3) δ: 1.03 (s, 9H), 3.06 (d,
1H, J ) 2.7 Hz), 3.71 (s, 3H), 4.10 (dd, 1H, J ) 2.7, 4.4 Hz),
6.79 (d, 2H, J ) 9.1 Hz), 7.18 (dd, 2H, J ) 9.1 Hz), 9.66 (d,
1H, J ) 4.4 Hz). 13C NMR (CDCl3) δ: 199.2, 164.3, 156.5, 131.1,
(22) Alcaide, B.; Dom´ınguez, G.; Escobar, G.; Parren˜o, U.; Plumet,
J . Heterocycles 1986, 24, 1579.
(23) Ferna´ndez, F.; Garc´ıa, G.; Rodr´ıguez, J . E. Synth. Commun.
1990, 20, 2837 and references therein.
(24) Full spectroscopy and analytical data for compounds not
included in this Experimental Section are described in the Supporting
Information.
(+)-(3S,4S)-4-(2-Met h oxyca r b on yl)et h en yl-1-(p -m et h -
oxyp h en yl)-3-[(S)-4-p h en yl-2-oxo-oxa zolid in -3-yl]-2-a ze-
tid in on e (10a ). Meth od E. From 0.20 g (0.55 mmol) of (+)-

Isomerization of cis-4-Formyl-2-azetidinones
J . Org. Chem., Vol. 65, No. 11, 2000 3459
3a , 0.15 g (67%) of (+)-10a was obtained after purification by
flash chromatography (hexane/AcOEt 2/1). Colorless oil. [R]D
AcOEt mixtures) to yield enaminones 6, 21, and 26. Spectro-
scopic and analytical data for some representative pure forms
of compounds 6, 21, and 26 follow.
1
) +183 (c 0.8, CHCl3). H NMR (CDCl3) δ: 3.61 (m, 1H), 3.64
(s, 3H), 3.72 (s, 3H), 4.31 (dd, 1H, J ) 6.3, 8.7 Hz), 4.69 (t, 1H,
J ) 8.7 Hz), 4.82 (d, 1H, J ) 2.4 Hz), 4.97 (dd, 1H, J ) 6.3,
8.7 Hz), 5.81 (dd, 1H, J ) 0.9, 15.6 Hz), 6.72 (d, 2H, J ) 9.3
Hz), 6.8 (dd, 1H, J ) 8.1, 15.6 Hz), 6.89 (d, 2H, J ) 9.3 Hz),
7.25 (m, 5H). 13C NMR (CDCl3) δ: 165.4, 160.2, 157.0, 156.8,
141.9, 137.5, 129.8, 129.5, 127.6, 124.5, 118.9, 114.3, 70.2, 66.0,
58.8, 57.9, 55.5, 51.9. IR (CHCl3) ν: 1757, 1710. MS m/z: 422
(M+, 69), 362 (69), 273 (66), 219 (100). Anal. Calcd for
C23H22N2O6: C, 65.40; H, 5.25; N, 6.63. Found: C, 65.62; H,
5.36; N, 6.91.
(+)-(3S,4S)-1-Ben zyl-3-[(S)-4-p h en yl-2-oxo-oxa zolid in -
3-yl]-4-(2-m eth oxyca r bon yl)eth en yl-2-a zetid in on e (10b).
Meth od E. From 0.20 g (0.57 mmol) of (+)-3b, 0.15 g (70%) of
(+)-10b was obtained after purification by flash chromatog-
raphy (hexane/AcOEt 2/1). Colorless oil. [R]D ) +24.8 (c 4,
CHCl3). 1H NMR (CDCl3) δ: 3.46 (dd, 1H, J ) 2.2, 8.1 Hz),
3.64 (s, 3H), 3.82 (d, 1H, J ) 15.1 Hz), 4.11 (dd, 1H, J ) 6.6,
8.8 Hz), 4.45 (d, 1H, J ) 15.1 Hz), 4.61 (t, 1H, J ) 8.8 Hz),
4.65 (d, 1H, J ) 2.2 Hz), 4.83 (dd, 1H, J ) 6.6, 8.8 Hz), 5.66
(d, 1H, J ) 15.8 Hz), 6.57 (dd, 1H, J ) 8.1, 15.8 Hz), 6.9 (m,
2H), 7.2 (m, 8H). 13C NMR (CDCl3) δ: 165.4, 163.6, 157.2,
142.1, 137.8, 137.0, 134.0, 129.5, 128.8, 128.0, 127.7, 127.1,
125.0, 70.7, 66.0, 59.0, 57.6, 51.9, 45.1. IR (CHCl3) ν: 1763,
1718. MS (m/z): 407 (M+ + 1, 8), 406 (M+, 6), 346 (65), 273
(100). Anal. Calcd for C23H22N2O5: C, 67.97; H, 5.46; N, 6.89.
Found: C, 68.20; H, 5.62; N, 7.10.
Com p ou n d (()-6. Reaction time: 3 h. From 0.10 g (0.34
mmol) of (()-1g or 0.11 g (0.34 mmol) of (()-1h , 0.06 g (80%)
of (()-6 was obtained after purification by flash chromatog-
raphy (hexane/AcOEt 2/1). White solid. Mp: 130-132 °C
(AcOEt/hexane). 1H NMR (CDCl3) δ: 3.56 (s, 3H), 3.81 (s, 3H),
5.16 (s, 1H), 5.77 (s, 1H), 6.90 (d, 2H, J ) 8.9 Hz), 7.10 (d, 2H,
J ) 8.9 Hz), 7.16 (br s, 1H). 13C NMR (CDCl3) δ: 172.8, 160.5,
157.0, 131.9, 121.8, 114.8, 99.8, 85.0, 55.5, 55.4. IR (KBr) ν:
1720, 1630. MS m/z: 236 (M+ + 1, 7), 235 (M+, 29), 204 (18),
203 (61), 174 (100). Anal. Calcd for C12H13NO4: C, 61.27; H,
5.57; N, 5.95. Found: C, 61.36; H, 5.68; N, 6.25.
Com p ou n d (()-21a . Reaction time: 3 h. From 0.23 g (0.82
mmol) of (()-20a , 0.20 g (95%) of (()-21a was obtained after
purification by flash chromatography (hexane/AcOEt 2/1).
Colorless oil. 1H NMR (CDCl3) δ: 0.74 (t, 3H, J ) 7.2 Hz),
1.88 (m, 2H), 3.42 (s, 3H), 3.75 (s, 3H), 5.56 (s, 1H), 6.10 (br s,
1H), 6.81 (d, 2H, J ) 8.8 Hz), 7.03 (d, 2H, J ) 8.8 Hz). 13C
NMR (CDCl3) δ: 170.0, 157.9, 155.1, 130.8, 126.0, 114.2, 101.0,
98.4, 55.5, 55.2, 16.0, 12.8. IR (CHCl3) ν: 1745, 1654, 1514.
MS m/z: 263 (M+, 46), 231 (57), 202 (100). Anal. Calcd for
C
14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.99; H,
6.27; N, 5.11.
Com p ou n d (()-21c. Reaction time: 3 h. From 0.60 g (2.19
mmol) of (()-20c, 0.47 g (80%) of (()-21c was obtained after
purification by flash chromatography (hexane/AcOEt 2/1).
Colorless oil. 1H NMR (CDCl3) δ: 3.44 (s, 3H), 3.84 (s, 3H),
5.78 (s, 1H), 6.55 (br s, 1H), 6.91 (d, 2H, J ) 8.8 Hz), 7.1 (d,
2H, J ) 8.8 Hz). 13C NMR (CDCl3) δ: 167.0, 158.3, 154.0, 129.1,
126.0, 114.3, 98.0, 90.7, 55.5, 55.5. IR (CHCl3) ν: 1757, 1654.
MS m/z: 271 (M+ 37Cl, 19), 270 (10), 269 (M+ 35Cl, 52), 209
(100). Anal. Calcd for C12H12NO4: C, 53.44; H, 4.49; N, 5.19.
Found: C, 53.26; H, 4.20; N, 4.92.
(()-tr a n s-3-ter t-Bu t yl-4-for m yl-4-d eu t er o-1-(p -m et h -
oxyp h en yl)-2-a zetid in on e (11). Meth od C (using CD3OD
1
as solvent). Reaction time: 3 h. Yield: 85%. H NMR (CDCl3)
δ: 1.02 (s, 9H), 3.06 (d, 1H, J ) 2.7 Hz), 3.71 (s, 3H), 6.79 (d,
2H, J ) 9.1 Hz), 7.18 (dd, 2H, J ) 9.1 Hz), 9.66 (d, 1H, J )
4.4 Hz). 13C NMR (CDCl3) δ: 199.2, 164.4, 156.5, 131.1, 117.5,
114.5, 63.5, 59.3 (t, J ) 95 Hz), 55.5, 31.5, 27.1. IR (CHCl3) ν:
1760, 1730.
Com p ou n d (()-26. Reaction time: 3 h. From 0.22 g (0.67
mmol) of (()-25, 0.11 g (60%) of (()-26 was obtained after
En a m in e 5b. A solution of 4-formyl-â-lactam 1e (1 mmol),
pyrrolidine (1 mmol), and R-phenylethylamine/ZnCl2 as cata-
lyst (0.05 mmol) in benzene (20 mL) was heated at reflux for
2 h using a Dean-Stark apparatus. Then the solvent was
removed under reduced pressure, and the product was char-
1
purification by flash chromatography (hexane/AcOEt 2/1). H
NMR (CDCl3) δ: 3.68 (s, 3H), 3.74 (s, 3H), 3.79 (s, 3H), 5.32
(s, 1H), 6.83 (d, 2H, J ) 9.3 Hz), 6.89 (d, 2H, J ) 9.3 Hz).
1
Ack n ow led gm en t. Support for this work by the
DGES-MEC (Project PB96-0565) is gratefully acknowl-
edged. Two of us (A.R.-V. and M.F.A.) acknowledge the
receipt of a predoctoral fellowship and a sabbatical
grant, respectively, from the DGES-MEC (Spain).
acterized without further purification. Colorless oil. H NMR
(CDCl3) δ: 1.09 (s, 9H), 1.63 (m, 4H), 2.66 (m, 4H), 3.42 (s,
1H), 3.80 (s, 3H), 5.35 (s, 1H), 6.8 (d, 2H, J ) 8.7 Hz), 7.5 (dd,
2H, J ) 8.7 Hz). 13C NMR (CDCl3) δ: 168.9, 156.9, 128.6, 123.1,
122.2, 115.1, 113.3, 64.6, 55.4, 54.7, 32.2, 27.1, 24.7. IR (CHCl3)
ν: 2960, 1736, 1510.
Gen er a l P r oced u r e for th e Syn th esis of En a m in on es
6, 21, a n d 26. A mixture of the starting cis-4-formyl- or cis-
4-acyl-â-lactam (1 mmol) and sodium carbonate (2 mmol) in
methanol (10 mL) was stirred at room temperature until
complete disappearance of the starting material (TLC). The
mixture was then concentrated, extracted with CH2Cl2, and
dried (MgSO4). After removal of the solvent, the crude mixture
was purified by column chromatography (silica gel, hexane/
Su p p or tin g In for m a tion Ava ila ble: Compound charac-
terization data and experimental procedures for products 1e,
(+)-2b, (+)-2d , 4a -c,f-h , (+)-7b, (+)-9d , (-)-9e, 12, (+)-18,
(+)-19, 20d ,e, 21b,d -f, 25, and 27-30, and Figures 1 and 2.
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