Entry to new conformationally constrained amino acids. First synthesis of 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinone derivatives via an intramolecular Nα-Cα-cyclization strategy

Article abstract of DOI:10.1021/jo015559b

A systematic study on the base-assisted intramolecular alkylation of N-benzyl-N-chloroacetyl amino acid derivatives is described. This study resulted in the first concise and versatile route to the preparation of 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinones, to be included into the scarce family of β-lactams with quaternary centers at the C₄ position. Particularly noteworthy is that the intramolecular N^α-C^α-cyclization of Phe and Leu derivatives afforded the corresponding β-lactam derivatives with moderate enantioselectivity (up to 56%). It is suggested that, in these particular cases, the cyclization reaction proceeds by way of planar enolate intermediates, which possess dynamic chirality. The described sequence of reactions, that is compatible with commonly used protecting moieties for the α-carboxy group, cannot be applied to dipeptides, since the cyclization to the six-membered 2,5-diketopiperazine ring occurrs preferentially.

Full text of DOI:10.1021/jo015559b

3538
J . Org. Chem. 2001, 66, 3538-3547
En tr y to New Con for m a tion a lly Con str a in ed Am in o Acid s. F ir st
Syn th esis of 3-Un su bstitu ted 4-Alk yl-4-ca r boxy-2-a zetid in on e
Der iva tives via a n In tr a m olecu la r Nr-Cr-Cycliza tion Str a tegy
Guillermo Gerona-Navarro, Maria Angeles Bonache, Rosario Herranz,
Maria Teresa Garc´ıa-Lo´pez, and Rosario Gonza´lez-Mun˜iz*
Instituto de Quı´mica Me´dica (CSIC), J uan de la Cierva 3, 28006 Madrid, Spain
iqmg313@iqm.csic.es
Received February 7, 2001
A systematic study on the base-assisted intramolecular alkylation of N-benzyl-N-chloroacetyl amino
acid derivatives is described. This study resulted in the first concise and versatile route to the
preparation of 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinones, to be included into the scarce family
of â-lactams with quaternary centers at the C4 position. Particularly noteworthy is that the
intramolecular NR-CR-cyclization of Phe and Leu derivatives afforded the corresponding â-lactam
derivatives with moderate enantioselectivity (up to 56%). It is suggested that, in these particular
cases, the cyclization reaction proceeds by way of planar enolate intermediates, which possess
dynamic chirality. The described sequence of reactions, that is compatible with commonly used
protecting moieties for the R-carboxy group, cannot be applied to dipeptides, since the cyclization
to the six-membered 2,5-diketopiperazine ring occurrs preferentially.
In tr od u ction
â-turns. The restriction of the φ dihedral angle could be
achieved through NR-CR-cyclizations,1 but scarce attention
has been paid to this kind of restricted amino acid
derivatives, and only some R-alkylprolines have been
studied in detail.2e,4 The small ring of the azetidine 1 (R-
alkyl-Aze) or azetidinone 2 (R-alkyl-Azn)5 should lead to
φ dihedral angle values of approximately 70 or -70°,
depending on the relative configuration of the respective
C2 or C4 stereogenic center. To the best of our knowledge,
only three references in the literature deal with the
synthesis of R-substituted azetidine- or azetidinone-R-
carboxylic acids, related to 1 and 2. Thus, Seebach group
reported the stereoselective synthesis of compounds 3a
and 3b (R-Et-Aze), by hydroxyalkylation of enantiopure
azetidine-2-carboxylic acid derivatives and NR-Cγ-cycliza-
tion of chiral amino acids, respectively.6,7 Compounds 4
and 5, prepared by asymmetric construction of the
quaternary C4 center via [2 + 2] cycloaddition reaction
of ketenes with ketimines,8 constitute the sole example
of 4-alkyl-4-carboxy-substituted â-lactams. In this pio-
neering approach, Palomo et al.8 used pyruvate imines
The interaction of peptides with macromolecular re-
ceptors is fundamental for many biological processes. The
successful transfer of information which occurs during
these events is highly dependent on the three-dimen-
sional conformation of peptides. Consequently, much
efforts have been directed toward the preparation of
locally or globally constrained peptide analogues.1 At the
local level this target can be achieved by modification of
individual residues via N-, R-, and â-alkylation of natural
amino acids and/or different cyclizations.2 However, due
to the difficulty to determine a priori the most appropri-
ate conformational restriction for a given peptide, pro-
cedures leading to structurally diversified nonproteino-
genic amino acids, from easily available starting materials,
could prove to be of great value.
In connection with our current interest in turn mimet-
ics,3 we were interested in conformationally constrained
amino acid derivatives, having the φ torsion angle
restricted to values near to those found in standard
(1) Giannis, A.; Ru¨bsam, F. Adv. Drug Res. 1997, 29, 1-78.
(2) For general reviews, see: (a) Morgan, B. A.; Gainor, J . A. Annu.
Rep. Med. Chem. 1989, 24, 243-252. (b) Toniolo, C. Int. J . Pept. Protein
Res. 1990, 35, 287-300. (c) Giannis, A.; Kolter, T. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1244-1267. (d) Cativiela, C.; D´ıaz-de-Villegas, M.
D. Tetrahedron: Asymmetry 1998, 9, 3517-3599. (e) Cativiela, C.;
D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645-732.
(3) (a) De la Figuera, N.; Alkorta, I.; Garc´ıa-Lo´pez, M. T.; Herranz,
R.; Gonza´lez-Mun˜iz, R. J . Chem. Soc., Chem. Commun. 1994, 613-
614. (b) De la Figuera, N.; Alkorta, I.; Garc´ıa-Lo´pez, M. T.; Herranz,
R.; Gonza´lez-Mun˜iz, R. Tetrahedron 1995, 51, 7841-7856. (c) Alkorta,
I.; Sua´rez, M. L.; Herranz, R.; Gonza´lez-Mun˜iz, R., Garc´ıa-Lo´pez, M.
T. J . Mol. Model. 1996, 2, 16-25. (d) Andreu, D.; Ruiz, S.; Carren˜o,
C.; Alsina, J .; Albericio, F.; J ime´nez, M. A.; De la Figuera, N.; Herranz,
R.; Garc´ıa-Lo´pez, M. T.; Gonza´lez-Mun˜iz, R. J . Am. Chem. Soc. 1997,
119, 10579-10586. (e) De la Figuera, N.; Mart´ın-Mart´ınez, M.;
Herranz, R.; Garc´ıa-Lo´pez, M. T.; Latorre, M.; Cenarruzabeitia, E.;
Del R´ıo, J .; Gonza´lez-Mun˜iz, R. Bioorg. Med. Chem. Lett. 1999, 9, 43-
48. (f) Mart´ın-Mart´ınez, M.; De la Figuera, N.; Latorre, M.; Herranz,
R.; Garc´ıa-Lo´pez, M. T.; Cenarruzabeitia, E.; Del R´ıo, J .; Gonza´lez-
Mun˜iz, R. J . Med. Chem. 2000, 43, 3770-3777.
(4) (a) Thaisrivongs, S.; Pals, D. T.; Lawson, J . A.; Turner, S. R.;
Harris, D. W. J . Med. Chem. 1987, 30, 536-541. (b) Hinds, M. G.;
Welsh, J . H.; Brennand, D. M.; Fischer, J .; Glennie, M. J .; Richards,
N. G. J .; Turner, D. L.; Robinson, J . A. J . Med. Chem. 1991, 34, 1177-
1189. (c) Fincham, C. I.; Horwell, D. C.; Ratcliffe, G. S.; Rees, D. C.
Bioorg. Med. Chem. Lett. 1992, 2, 403-406. (d) Bisang, C.; Weber, C.;
Inglis, J .; Schiffer, C. A.; van Gunsteren, W. F.; J elesarov, I.; Bosshard,
H. R.; Robinson J . A. J . Am. Chem. Soc. 1995, 117, 7904-7915.
(5) For easy of naming, the symbol Aze is generally accepted to
describe azetidine-2-carboxylic acid. Here we propose the symbol Azn
to describe 2-azetidinone-4-carboxylic acids, in a similar way to the
incorporation of a final “n” letter in Asn and Gln, that serves to
distinguish asparagine and glutamine, with a carboxamide side chain,
from Asp and Glu.
(6) Seebach, D.; Vettiger, T.; Mu¨ller, H.M.; Plattner, D. A.; Petter,
W. Liebigs Ann. Chem. 1990, 687-695.
(7) Seebach, D.; Dziadulewicz, E.; Behrendt, L.; Cantoreggi, S.; Fitzi,
R. Liebigs Ann. Chem. 1989, 1215-1232.
(8) Palomo, C.; Aizpurua, J . M.; Garc´ıa, J . M.; Galarza, R.; Legido,
M.; Urchegui, R.; Roma´n, P.; Luque, A.; Server-Carrio´, J .; Linden, A.
J . Org. Chem. 1997, 62, 2070-2079.
10.1021/jo015559b CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/21/2001

Synthesis of 4-Alkyl-4-carboxy-2-azetidinones
J . Org. Chem., Vol. 66, No. 10, 2001 3539
Ch a r t 1. Con for m a tion a lly Restr icted Am in o
Acid s by Cycliza tion to Azetid in e or Azetid in on e
Rin gs
and chiral ketenes, required for the asymmetric induc-
tion, to obtain the 3,4,4-trisubstituted 2-azetidinones 4
and 5 with moderate to good diastereoselectivity. How-
ever, methods for the synthesis of 3-unsubstituted 4-alkyl-
4-carboxy-2-azetidinones 2 could not be found in the
literature, and therefore their preparation constitutes a
synthetic challenge. Apart from our particular interest
in compounds 1 and 2 as conformationally restricted
amino acid derivatives, the multiple chemical transfor-
mations described for â-lactams9 suggested that Azn
derivatives 2 could also be useful building blocks to create
molecular diversity. In close connection with our work,
the use of azetidine and azetidinone derivatives as
structural units for incorporating conformational re-
straints into peptides,10 and as synthetic intermediates
in the preparation of secondary structure mimetics,11 has
gained importance in recent years.
To address the possibility of the synthesis of 3-unsub-
stituted 4,4-disubstituted 2-azetidinones 2, we recently
reported the preparation of new conformationally con-
strained tryptophan derivatives (2, R1 ) CH2In) and their
ulterior transformation into the corresponding azetidines
1.12 For such purpose, we designed a synthetic strategy
involving, as the key step, the formation of the C3-C4
bond of the â-lactam ring.13 This was achieved through
base-promoted intramolecular alkylation of the corre-
sponding easily available NR-benzyl-NR-chloroacetyl-
substituted Trp derivatives. To evaluate the versatility
of this new synthetic strategy, we have next undertook
a systematic study on the intramolecular alkylation of
different N-benzyl-N-chloroacetyl-derived amino acids.
This paper deals with the scope and limitation of this
new synthetic procedure toward 4,4-disubstituted 2-aze-
tidinones, derived from representative aromatic (Phe),
aliphatic (Ala, Leu), acidic (Glu), and basic (Orn) amino
acids. The preparation of 4-carboxy-2-azetidinones from
Gly derivatives, the compatibility of different R-carboxy
derivatives (OtBu, OMe, OBzl, NHR) with the proposed
sequence of reactions, and the selective C- and N-
deprotection have also been investigated.
Resu lts a n d Discu ssion
Although N-unsubstituted 2-azetidinones were our
final goal, NR-benzyl- or NR-(p-methoxy)benzyl-NR-chlo-
roacetyl amino acid derivatives 7, that would provide
1-substituted 2-azetidinones 8, were initially selected for
two reasons: an N-alkyl group should constrain the
amide moiety of 7 to a cisoid conformation that might
allow the amino acid derivative to cyclize easily,14,15 and
these N-benzyl protecting groups can be readily removed
from azetidinones.16 As shown in Scheme 1, the starting
derivatives 7 were prepared, in almost quantitative yield,
by reaction of the corresponding NR-benzyl- or NR-(p-
methoxy)benzyl amino acid alkyl ester 6 with chloro-
acetyl chloride, using propylene oxide as HCl scavenger.
On the basis of the previous result with Trp,12 NaH
and Cs2CO3 were chosen as bases to promote the cycliza-
tion of the NR-chloroacetyl derivatives 7 to the â-lactams
8. Independently on the starting amino acid, Cs2CO3
worked better than NaH, especially for methyl ester
derivatives in which the last base induced a considerable
extent of saponification (Table 1).17 In general, using Cs2-
CO3 longer reaction times were required for the complete
disappearance of the starting chloroacetyl derivatives
than with NaH. The described sequence of reactions is
compatible with most of the protecting moieties com-
monly used for the R-carboxy group, and similar yields
were obtained in the generation of the tert-butyl, methyl,
and benzyl ester Phe derivatives 8c, 8d , and 8e. Regard-
ing the starting amino acid, Phe-, Ala-, Glu-, and Orn-
derived compounds afforded satisfactory yields of the
corresponding 2-azetidinones. However, for the Gly and
Leu analogues incomplete or complex reactions were
found, the yields being higher for methyl ester derivatives
(9) For some selected reviews, see: (a) Ojima, I. In The Organic
Chemistry of â-Lactams; Georgs, G. I., Ed; VCH: New York, 1992; pp
197-255. (b) Palomo, C.; Aizpurua, J . M.; Gamboa, I. In Enantiose-
lective Synthesis of â-Amino Acids; J uaristi, E., Ed.; Wiley-VCH: New
York, 1996, pp 279-357.
(10) For some leading references, see: (a) Sreenivassan, U.; Mishra,
R. K.; J ohnson, R. L. J . Med. Chem. 1993, 36, 256-263. (b) Palomo,
C.; Aizpurua, J . M.; Galarza, R.; Mielgo, A. Chem. Commun. 1996,
633-634. (c) Palomo, C.; Gamboa, I.; Cuevas, C.; Boschetti, C.; Linden,
A. Tetrahedron Lett. 1997, 38, 4643-4646. (d) Linder, M. R.; Podlech,
J . Org. Lett. 1999, 1, 869-872. (e) Palomo, C.; Aizpurua, J . M.; Benito,
A.; Galarza, R.; Khamrai, U. K.; Vazquez, J .; De Pascual-Teresa, B.;
Nieto, P. M.; Linden, A. Angew. Chem., Int. Ed. 1999, 38, 3056-3058.
(f) Hanessian, S.; Bernstein, N.; Yang, R.Y.; Maguire, R. Bioorg. Med.
Chem. Lett. 1999, 9, 1437-1442. (g) Palomo, C.; Aizpurua, J . M.;
Galarza, R.; Benito, A.; Khamrai, U. K.; Eikeseth, U.; Linden, A.
Tetrahedron 2000, 56, 5563-5570.
(11) (a) Qabar, M. N.; Kahn, M. Tetrahedron Lett. 1996, 37, 965-
968. (b) Kim, H.O.; Lum, C.; Lee, M. S. Tetrahedron Lett. 1997, 38,
4935-4938. (c) Qabar, M. N.; Meara, J . P.; Ferguson, M. D.; Lum, C.;
Kim, H.O.; Kahn, M. Tetrahedron Lett. 1998, 39, 5895-5898.
(12) Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.; Garc´ıa-Lo´pez,
M. T.; Gonza´lez-Mun˜iz, R. Synlett 2000, 1249-1252.
(13) This approach was guided by two synthetic precedents, both
concerning the preparation of 4,4-diethoxycarbonyl substituted â-lac-
tams from the corresponding malonate derivatives: (a)Sheehan, J . C.;
Bose, A. K. J . Am. Chem. Soc., 1951, 73, 1761. (b)Simig, G.; Fetter, J .;
Hornyak, G.; Zauer, K.; Doleschall, G.; Lempert, K.; Nyitrai, J .;
Gombos, Z.; Gizur, T.; Barta-Szalai, G.; Kajtar-Peredy, M. Acta Chim.
Hung. 1985, 119, 17-32.
(14) For recent examples on the effect of the N-substitution in
promoting cyclizations, see: (a) Ehrlich, A.; Heyne, H.U.; Winter, R.;
Beyermann, M.; Haber, H.; Carpino, L. A.; Bienert, M. J . Org. Chem.
1996, 61, 8831-8838. (b) El Mahdi, O.; Lavergne, J .P.; Vialefont, P.;
Martinez, J .; Riche, C. Synth. Commun. 1997, 27, 3539-3545. (c) El
Mahdi, O.; Lavergne, J .P.; Martinez, J .; Vialefont, P.; Essassi, E. M.;
Riche, C. Eur. J . Org. Chem. 2000, 251-255.
(15) In our hands, attempts to cyclize NR-chloroacetyl-L-Phe-OtBu
by using NaH or Cs2CO3 either in MeCN or DMF resulted unsuccessful.
(16) Wild, H. In The Organic Chemistry of â-Lactams; Georgs, G.
I., Ed; VCH: New York, 1992; pp 1-48.
(17) Hydrolysis of the chloroacetyl group in compounds 7 to the
starting N-benzyl derivatives 6 was observed in reactions performed
with NaH, but not with Cs2CO3. The extent of this hydrolysis range
from 10 to 30%.

3540 J . Org. Chem., Vol. 66, No. 10, 2001
Gerona-Navarro et al.
Ta ble 1. Syn th esis of 1,4,4-Tr isu bstitu ted 2-Azetid in on es
8 Der ived fr om Differ en t Am in o Acid s.
Ch a r t 2. P r od u cts Resu ltin g fr om In tr a m olecu la r
O-Alk yla tion
start.
time
8a (9)a
compd
R1
CH2Ph
R2
R3
base
solvent (days)
(%)
7a
7b
7c
7c
7d
7d
7e
7e
7f
7f
7g
7h
7i
tBu Bzl NaH
Me Bzl NaH
tBu Pmb NaH
tBu Pmb Cs2CO3 MeCN
Me Pmb Cs2CO3 MeCN
Me Pmb Cs2CO3 DMF
Bzl Pmb Cs2CO3 MeCN
Bzl Pmb Cs2CO3 DMF
MeCN
MeCN
MeCN
1
1
1
7
6
1
7
2
1
62
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
H
H
H
CH3
CH3
30b
53
71
74
68 (6)
75
Sch em e 2. Selective C- a n d N-Dep r otection
Rea ction sa
68 (7)
32 (10)c
23 (18)d
54 (19)
60
tBu Pmb NaH
MeCN
tBu Pmb Cs2CO3 MeCN 10
Me Pmb Cs2CO3 MeCN 10
tBu Bzl NaH
Me Bzl NaH
Me Bzl Cs2CO3 MeCN
tBu Pmb NaH
MeCN
MeCN
1
1
8
38e
69
7i
7j
7j
7k
7l
CH3
CH2(CH3)2
CH2(CH3)2
CH2(CH3)2
MeCN 10
tBu Pmb Cs2CO3 MeCN 20
Me Pmb Cs2CO3 MeCN 15
38 (11)f
19 (16)g
35 (16)
11h
(CH2)2CO2tBu Me Pmb NaH
MeCN
1
4
1
7l
7m
(CH2)2CO2tBu Me Pmb Cs2CO3 MeCN
65
72
(CH2)3NHZ
Bzl Pmb Cs2CO3 MeCN
a
b
Yield of isolated compounds. Compound 10a (30%) was also
isolated. c Unaltered 7f (6%) was recovered. Unaltered 7f (41%)
d
was recovered. e Compound 10g (15%) was also isolated. f Unal-
g
tered 7j (7%) was recovered. Unaltered 7j (12%) was recovered.
h
Hydrolysis of the methyl ester was observed (≈24%, estimated
by HPLC).
Sch em e 1. Syn th esis of
4-Alk yl-4-ca r boxy-2-a zetid in on es fr om Am in o
Acid sa
a
Reagents and conditions: (a) TFA/CH2Cl2, rt, 2 h. (b) 1. 2 N
NaOH/MeOH, rt, overnight. (c) H2/Pd-C/EtOAc, rt, 7 h. (d) Li/
NH3, -78 °C, 5 min. (e) K2S2O8/K2HPO4/MeCN-H2O, 75 °C, 3-5
h. (f) CH2N2/Et2O, 0 °C, 30 min
sponding free carboxylic acid derivatives 10 can be easily
obtained by using conventional hydrolysis procedures,
t
such as acid treatment (R2 ) Bu) or saponification (R2
) Me), and hydrogenolysis (R2 ) Bzl). With regard to the
N-deprotection, H-R-Bzl-Azn-OH (11a ) was prepared
from 10a in 60% yield by reductive debenzylation using
Li in NH3.18 In this method, the free carboxylic acid was
required in order to avoid carboxamide formation. Re-
moval of the p-methoxybenzyl group in 8c and 8d was
readily achieved by treatment with K2S2O8,19 to give H-R-
Bzl-Azn-OtBu (11c) and H-R-Bzl-Azn-OMe (11d ), keeping
the R-carboxy protection.
To evaluate the enantioselectivity, if any, of the in-
tramolecular alkylation reaction, 2-azetidinone-4-car-
boxylic acids 10a , 10c, 10h , and 10k , obtained after
hydrolysis of the corresponding alkyl esters 8a , 8c (8d ),
8h , and 8k , were transformed into the dipeptide deriva-
tives 12 and 13 (Scheme 3, Table 2).20,21 Since NOE
experiments performed with 12 and 13 resulted incon-
clusive, the tentative assignment of the configuration at
C4 position in these compounds was based on the chemi-
cal shifts of the â-H protons of the aliphatic residue,22,23
and on their respective retention times in the HPLC
a
Reagents and conditions: (a) ClCH2COCl/propylene oxide/
THF, rt, 1-2 h. (b) Base/solvent (see Table 1)
than for tert-butyl esters. In both cases, the respective
azetidinones were obtained along with the corresponding
2,5-dioxoperhydrooxazines 9f (10-19%) and 9j (11-16%),
resulting from the intramolecular O-alkylation of the
corresponding enolate intermediate (Table 1). However,
in the case of Phe, Ala, Glu, and Orn derivatives, this
O-alkylation was not especially significant using MeCN
as solvent. The competing oxazine formation become
higher when the cyclization was carried out in DMF, as
observed in the reaction of the Phe N-chloroacetyl deriva-
tives 7d and 7e (Compound 9d , Chart 2, Table 1).
With the 1,4,4-trisubstituted 2-azetidinones 8 in hand,
the next question we addressed was the selective removal
of C- and N-protecting groups (Scheme 2). As demon-
strated for compounds 8a -e, 8g, 8h , and 8k , the corre-
(18) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1985, 26, 3783-
3786.
(19) Podlech, J .; Linder, M. R. J . Org. Chem. 1997, 62, 5873-5883.
(20) Optical rotation values of zero for Ala- (8h , 8i), Glu- (8l), and
Orn-derived (8m ) azetidinones indicated no enantioselectivity in the
cyclization reactions affording these compounds.
(21) To avoid kinetic resolution, the coupling reactions were con-
ducted with large excesses of the amino acid and of the coupling agent
(BOP), until complete disappearance of the azetidinone derivative 10
(quantified by HPLC).

Synthesis of 4-Alkyl-4-carboxy-2-azetidinones
J . Org. Chem., Vol. 66, No. 10, 2001 3541
Sch em e 3. Syn th esis of Dip ep tid e Der iva tivesa
Sch em e 4. Mem or y of Ch ir a lity: Asym m etr ic
Meth yla tion of (S)-P h e Der iva tives a n d P r op osed
Ch ir a l In ter m ed ia tes
a
Reagents and conditions: (a) H-L-Ala-OMe or H-L-Phe-OMe/
BOP/TEA/THF, rt
Ta ble 2. Ster eoselectivity in th e F or m a tion of
1,4,4-Tr isu bstitu ted 2-Azetid in on es
entry starting compd
yield (%)a 12+13
12:13b ratio de
1
2
3
4
5
6
7
10a c
10cc
10cd
10ce
10cf
10h f
10k g
83
89
86
82
88
82
86
67:33
67:33
78:22
78:22
65:35
50:50
71:29
34
34
56
56
30
0
42
their corresponding Phe analogues (entry 3). Diastere-
oisomeric excesses up to 47% were previously found in
the formation Trp-derived 2-azetidinones.12 On the con-
trary, reaction of 10h with H-L-Phe-OMe led to the
corresponding dipeptides 12h and 13h in a ratio of 50:
50, indicating that the formation of the precursor Ala-
derived azetidinone 8h proceeded without stereoselection.
a
b
Yield of isolated compounds. Measured by HPLC. c Obtained
from the corresponding tBu-substituted azetidinone, previously
generated with NaH in MeCN. Obtained from the tert-butoxy-
carbonyl derivative 8c, previously generated with Cs2CO3 in
CH3CN. e Obtained from the methoxycarbonyl derivative 8d ,
previously generated with Cs2CO3 in CH3CN. f Obtained from
d
g
compound 8d , previously generated with Cs2CO3 in DMF. Ob-
tained from compound 8k , previously generated with Cs2CO3 in
CH3CN.
It has been described that N-methyl-N-Boc-(S)-pheny-
lalanine alkyl esters 14 can be converted into enantio-
merically enriched R-methyl derivatives 15 by direct
alkylation, without employing any external chiral source
(Scheme 4).25 This enantioselectivity can be ascribed to
the preservation of the information on chirality of the
starting material in the intermediate anionic species for
a limited time.26 Taking into account that N-benzyl-N-
chloroacetyl amino acid derivatives 7 share certain
structural features of 14, our results imply that the
stereochemical course of the intramolecular alkylation
of 7a , 7c, and 7k , leading to the 2-azetidinones 8a , 8c,
and 8k , is similar to that reported for the asymmetric
methylation of 14 to give 15, according to this recently
proposed concept of the memory of chirality. The stereo-
selectivity observed in the case of Phe, Leu, and Trp
derivatives could be explained in terms of the existence
of chiral enolate intermediates, such as those proposed
by Fuji et al. and depicted in Scheme 4.26 In our case,
the implication of enolate B as intermediate in the
â-lactam formation can be discarded because the in-
tramolecular alkylation of 7 to 8 requires an amide cis-
rotamer, while the coordination of the metal cation by
the carbonyl oxygen in B fixes the amide bond in a
transoid conformation, incompatible with the creation of
the four-membered ring.
chromatograms.24 As shown in Table 2, coupling of Phe-
derived compounds 10a and 10c, coming from the cor-
responding tert-butoxycarbonyl derivative and NaH-
induced cyclization, with enantiomerically pure H-L-Ala-
OMe, led to the formation of dipeptides 12a and 12c,
respectively, in 34% de, independently of the 1-substitu-
ent. In the Cs2CO3-promoted cyclizations, the ratio of
diastereoisomeric dipeptide derivative 12c was the same
when 10c came from the methyl ester derivative 8d than
when it arose from the tert-butyl ester analogue 8c (Table
2, entries 3 and 4). By contrast, the stereoselectivity was
much higher when CH3CN was used as solvent than in
the case of DMF (compare entries 4 and 5). The diaster-
eomeric excess was increased by 22% when the formation
of the starting 4-benzyl-2-azetidinone was induced by Cs2-
CO3 (entry 4), compared to NaH (entry 2), showing the
importance of the countercation on the observed stereo-
selectivity. Concerning the effects of the R1 substituent,
Leu-derived dipeptides 12k and 13k were obtained in a
71:29 ratio (42% de, entry 7), lower than that found for
(22) 1H NMR studies on stereoisomeric dipeptides composed by one
aromatic amino acid and one aliphatic amino acid, showing that the
methyl or methylene protons of the aliphatic residue are more shielded
in the D-L and L-D dipeptides than in the L-L and D-D analogues: (a)
Deber, C. M.; J oshua, M. Biopolymers 1972, 11, 2493-2503. (b) Garc´ıa-
Lo´pez, M. T.; Gonza´lez-Mun˜iz, R.; Molinero, M. T. Del R´ıo, J . J . Med.
Chem. 1988, 31, 295-300. (c) Gonza´lez-Mun˜iz, R.; Cornille, F.;
Bergeron, F.; Ficheux, D.; Pothier, J .; Durieux, C.; Roques, B. P. Int
J . Pept. Protein Res. 1991, 37, 331-340.
(23) Taking into account that the CH2CO branch of the â-lactam
ring has preference over the benzyl, isobutyl, or methyl groups, 4R-
isomers show the same spatial disposition as in L-amino acids, while
4S-isomers correspond to D-configured amino acids.
To evaluate the possible preparation of 2-azetidinones
from dipeptides, the cyclization of Phe-Ala dipeptide
derivative 17 was finally investigated (Scheme 5). Under
the general conditions previously used for amino acid
(24) In dipeptides and retrodipeptides, it was shown that hetero-
chiral (L-D or D-L) derivatives are more retained than homochiral (L-L
or D-D) analogues: Fournie´-Zaluski, M. C.; Lucas-Soroca, E.; Devin,
J .; Roques, B. P. J . Med. Chem. 1986, 29, 751-757.
(25) Kawabata, T.; Wirth, T.; Yahiro, K.; Suzuki, H.; Fuji, K. J . Am.
Chem. Soc. 1994, 116, 10809-10810.
(26) For a general review on the memory of chirality, see: Fuji, K.;
Kawabata, T. Chem. Eur. J . 1998, 4, 373-376.

3542 J . Org. Chem., Vol. 66, No. 10, 2001
Gerona-Navarro et al.
Exp er im en ta l Section
Sch em e 5. Ba se-Assisted Cycliza tion of a n
N-Ch lor oa cetyl Dip ep tid e Der iva tivea
All reagents were of commercial quality. Solvents were dried
and purified by standard methods. Amino acid derivatives
were obtained from Bachem AG or Neosystem. 1H NMR
spectra were recorded with a Varian Gemini 200 or a Varian
Unity 300 spectrometers operating at 200 and 300 MHz,
respectively, using TMS as internal standard. 13C NMR spectra
were registered on a Varian Gemini 200 (50 MHz) or a Varian
Unity 300 (75 MHz). Electospray mass spectra (positive mode)
were recorded with a Hewlett-Packard 1100SD spectrometer.
Elemental analyses were obtained on a CHN-O-RAPID
instrument. Analytical TLC was performed on aluminum
sheets coated with a 0.2 mm layer of silica gel 60 F254 (Merck).
Silica gel 60 (230-400 mesh, Merck) was used for column
chromatography. Analytical HPLC was performed on a Waters
Nova-pak C18 (3.9 × 150 mm, 4 µm) column, with a flow rate
of 1 mL/min, using a tuneable UV detector set at 214 nm.
Mixtures of MeCN (solvent A) and 0.05% TFA in H2O (solvent
B) were used as mobile phase. N-Benzyl and N-(p-methoxy)-
benzyl derivatives 6 were obtained by reaction of the corre-
sponding amino acid alkyl ester and benzaldehyde or p-meth-
oxybenzaldehyde, followed by reduction with NaBH4.28
a
Reagents and conditions: (a) ClCH2COCl/propylene oxide/
THF, rt, 1 h. (b) NaH/MeCN, rt, 20 min. (c) Cs2CO3/MeCN, rt, 2
h.
Syn th esis of N-Ch lor oa cetyl Am in o Acid Der iva tives
7. Gen er a l P r oced u r e. A solution of the corresponding
N-benzyl or N-(p-methoxybenzyl) amino acid derivative 6 (4
mmol) in THF (20 mL) was treated with propylene oxide (4.2
mL, 60 mmol) and chloroacetyl chloride (0.47 mL, 6 mmol).
After stirring at room temperature for 1-2 h, the solvents were
evaporated, and the resulting residue was purified on a silica
gel column, using the solvent system specified in each case.
N-Ben zyl-N-ch lor oa cetyl-L-P h e-OtBu (7a ). Yield: 97%.
Eluent: EtOAc/hexane (1:30). HPLC: tR ) 15.36 min (A:B )
derivatives (Cs2CO3, CH3CN), compound 17 mainly af-
forded diasteromerically pure 2,5-diketopiperazine 18,27
indicating that cyclization to the six-membered ring is
much faster than competing ring closure to â-lactams 14c
and 15c (14c + 15c ≈ 2%, determined by HPLC). In our
previous communication on Trp-derived 2-azetidinones,
we found that the â-lactam formation did not compete
with the cyclization to a seven-membered diazepine
ring.12
1
50:50). [R]D ) -126.2 (c ) 1.11, CHCl3). H NMR (300 MHz,
CDCl3): rotamers ratio29 (7:1) δ major rotamer 7.33-7.13 (m,
10H), 4.49 (d, 1H, J ) 16.8), 4.10 (m, 1H), 3.98 (m, 2H), 3.73
(d, 1H, J ) 16.8), 3.34 (dd, 1H, J ) 14.0, 5.6), 3.24 (dd, 1H, J
) 14.0, 9.5), 1.43 (s, 9H). 13C NMR (75 MHz, CDCl3): major
rotamer δ 168.53, 166.62 137.95, 135.41, 129.32, 128.59,
128.52, 127.81, 127.33, 126.63, 81.84, 62.54, 52.89, 41.29 34.85,
27.81. MS (ES, positive mode): 388.3 (M+ + 1). Anal. Calcd
for C22H26ClNO3: C, 68.12; H, 6.76; Cl, 9.14; N, 3.61. Found:
C, 67.92; H, 6.91; Cl, 9.08; N, 3.47.
Con clu sion s
In the present study, we have demonstrated that
3-unsubstituted 4-alkyl-4-carboxy-2-azetidinones can be
readily prepared via intramolecular alkylation of N-
benzyl-N-chloroacetyl amino acid derivatives. This ap-
proach provides for the first time a wide variety of
4-alkyl-4-carboxy-2-azetidinones, that by themselves, or
after transformation into the corresponding azetidines,12
could be considered as new conformationally constrained
amino acids with fixed φ dihedral angles. Additional
attractive features of this approach include an expanded
scope of â-lactam chemistry and the potential use of these
2-azetidinones to create molecular diversity, after ap-
propriate chemical transformations. Of particular inter-
est in this synthesis is the observed enantioselectivity
during the â-lactam ring formation in Trp, Phe, and Leu
derivatives (up to 56%), constituting novel examples of
asymmetry due to the memory of chirality.14 This selec-
tivity was dependent on the R1 group, and on the base
and solvent used. Although the enantioselectivity was
only moderate, it is expected that application of other
asymmetric protocols, such as chiral auxyliaries of chiral
phase-transfer catalysts, to this convenient procedure
could result in more enantioselective ways to this kind
of 4,4-disubstituted 2-azetidinones. Work in this direction
is ongoing in our laboratories.
N-Ben zyl-N-ch lor oa cet yl-L-P h e-OMe (7b ). 90%. Elu-
ent: gradient from 8 to 30% of EtOAc in hexane. HPLC: tR
)
1
9.58 min (A:B ) 45:55). [R]D ) -126.7 (c ) 0.45, CHCl3). H
NMR (300 MHz, CDCl3): rotamers ratio (7:1) δ major rotamer
7.35-7.15 (m, 10H), 4.50 (d, 1H, J ) 16.7), 4.24 (dd, 1H, J )
9.5, 5.7), 4.01 (m, 2H), 3.80 (d, 1H, J ) 16.7), 3.68 (s, 3H),
3.38 (dd, 1H, J ) 14.0, 5.7), 3.27 (dd, 1H, J ) 14.0, 9.5). 13C
NMR (75 MHz, CDCl3): major rotamer δ 170.09, 167.02,
137.68, 135.31, 129.50, 128.91, 128.79, 128.11, 127.41, 126.99,
61.68, 52.76, 52.30, 41.43, 34.85. MS (ES, positive mode): 346.2
(M+ + 1). Anal. Calcd for C19H20ClNO3: C, 65.99; H, 5.83; Cl,
10.25; N, 4.05. Found: C, 65.88; H, 5.71; Cl, 9.98; N, 3.85.
N-(p-Meth oxyben zyl)-N-ch lor oa cetyl-L-P h e-OtBu (7c).
Yield: 99%. Eluent: EtOAc/hexane (1:3). HPLC: tR ) 13.92
1
min (A:B ) 50:50). [R]D ) -111.6 (c ) 1.15, CHCl3). H NMR
(300 MHz, CDCl3): rotamers ratio (10:1) δ major rotamer
7.28-6.74 (m, 9H), 4.37 (d, 1H, J ) 16.2), 4.01 (m, 1H), 3.98
(m, 2H), 3.73 (s, 3H), 3.59 (d, 1H, J ) 16.2), 3.25 (m 2H), 1.40
(s, 9H). 13C NMR (75 MHz, CDCl3): major rotamer δ 168.35,
166.20, 158.98, 137.90, 129.10, 128.69, 128.27, 126.89, 126.37,
113.67, 81.41, 62.06, 54.95, 52.39, 41.15, 34.52, 27.60. MS (ES,
positive mode): 440.1 (M+ + Na). Anal. Calcd for C23H28
-
ClNO4: C, 66.10; H 6.75; Cl, 8.48; N, 3.35. Found: C, 66.01;
H, 6.95; Cl, 8.44; N, 3.26.
N-(p-Meth oxyben zyl)-N-ch lor oa cetyl-L-P h e-OMe (7d ).
Yield: 99%. Eluent: EtOAc/hexane (1:4). HPLC: tR ) 8.43 min
(27) Using NaH as base, compound 18 was obtained as an epimeric
mixture at C3, in an 84:16 3S/3R ratio. In the 1H NMR spectrum of
the epimeric mixture, the 1′-methyl group of minor 3R-isomer appeared
as a doublet at 0.87 ppm, while in the 3S-epimer the chemical shift of
these protons was 1.09 ppm.
(28) Weygand, F.; Steglich, W.; Bjarnarsson, J .; Akhtar, R.; Chytill,
N. Chem. Ber. 1968, 101, 3623-3641.
(29) Rotamers ratio was measured by 1H NMR. In general, main
differences between major and minor rotamers were found for R-CH,
N-CH2, and OtBu or OMe protons.

Synthesis of 4-Alkyl-4-carboxy-2-azetidinones
J . Org. Chem., Vol. 66, No. 10, 2001 3543
1
(A:B ) 45:55). [R]D ) -131.1 (c ) 1.11, CHCl3). H NMR (300
mode): 384.5 (M+ + 1). Anal. Calcd for C20H30ClNO4: C, 62.57;
H, 7.88; Cl, 9.23; N, 3.65. Found: C, 62.68; H, 7.84; Cl, 9.03;
N, 3.28.
MHz, CDCl3): rotamers ratio (9:1) δ major rotamer 7.27-6.75
(m, 9H), 4.36 (d, 1H, J ) 16.3), 4.12 (m, 1H), 4.00 (m, 2H),
3.71 (s, 3H), 3.66 (d, 1H, J ) 16.3), 3.61 (s, 3H), 3.29 (m 2H).
13C NMR (75 MHz, CDCl3): major rotamer δ 169.73, 166.44,
158.92, 137.33, 128.98, 128.52, 128.21, 126.48, 126.39, 113.66,
60.99, 55.08, 52.44, 52.08, 41.46, 34.61. MS (ES, positive
mode): 398.1 (M+ + Na). Anal. Calcd for C20H22ClNO4: C,
63.91; H, 5.90; Cl, 9.43; N, 3.73. Found: C, 64.05; H, 5.64; Cl,
9.29; N, 3.57.
N-(p-Meth oxyben zyl)-N-ch lor oa cetyl-L-P h e-OBzl (7e).
Yield: 83%. Eluent: gradient from 6 to 15% of EtOAc in
hexane. HPLC: tR ) 12.91 min (A:B ) 50:50). [R]D ) -124.0
(c ) 1.12, CHCl3). 1H NMR (300 MHz, CDCl3): rotamers ratio
(10:1) δ major rotamer 7.27-6.56 (m, 14H), 5.01 (m, 2H), 4.31
(d, 1H, J ) 16.4), 4.04, (m, 1H), 3.92 (m, 2H), 3.65 (s, 3H),
3.50 (d, 1H, J ) 16.4), 3.27 (m, 2H). 13C NMR (75 MHz,
CDCl3): major rotamer δ 169.27, 166.59, 159.16, 137.63,
135.36, 129.28, 128.77, 128.49, 128.32, 128.10, 126.67, 113.88,
67.06, 61.65, 55.06, 52.62, 41.23, 34.63. MS (ES, positive
mode): 474.1 (M+ + Na). Anal. Calcd for C26H26ClNO4: C,
69.10; H, 5.80; Cl, 7.84; N, 3.10. Found: C, 68.86; H, 5.90; Cl,
7.73; N, 2.95.
N-(p-Meth oxyben zyl)-N-ch lor oa cetyl-L-Leu -OMe (7k ).
Yield: 100%. Eluent: EtOAc/hexane (1:4). HPLC: tR ) 12.05
1
min (A:B ) 40:60). [R]D ) -55.5 (c ) 1.09, CHCl3). H NMR
(300 MHz, CDCl3): rotamers ratio (3.2:1) δ major rotamer
7.11-6.80 (m, 4H), 4.66 (m, 1H), 4.55 (d, 1H, J ) 17.1), 4.42
(d, 1H, J ) 17.1), 3.97 (s, 2H), 3.71 (s, 3H), 3.54 (s, 3H), 1.78
(m, 1H), 1.51 (m, 2H), 0.81 (d, 3H, J ) 6.1), 0.73 (d, 3H, J )
6.2). 13C NMR (75 MHz, CDCl3): major rotamer δ 171.43,
167.53, 159.21, 129.21, 127.99, 114.18, 56.52, 55.23, 52.06,
49.91, 41.77, 38.06, 24.98, 22.51, 22.09. MS (ES, positive
mode): 364.3 (M+ + Na). Anal. Calcd for C17H24ClNO4: C,
59.73; H, 7.08; Cl, 10.37; N, 4.10. Found: C, 59.57; H, 7.23;
Cl, 9.98; N, 4.00.
N -(p -Me t h oxyb e n zyl)-N -ch lor oa ce t yl-L-Glu (Ot Bu )-
OMe (7l). Yield: 82%. Eluent: EtOAc/hexane (1:10). HPLC:
tR ) 16.60 min (A:B ) 41:59). [R]D ) -53.36 (c ) 1.02, CHCl3).
1H NMR (200 MHz, CDCl3): rotamers ratio (3.2:1) δ major
rotamer 7.24-6.87 (m, 4H), 4.57 (m, 2H), 4.36 (m, 1H), 4.06
(m, 2H), 3.79 (s, 3H), 3.62 (s, 3H), 2.29-1.85 (m, 4H), 1.40 (s,
9H). 13C NMR (75 MHz, CDCl3): major rotamer δ 171.99,
170.41, 167.17, 159.25, 128.37, 127.29, 114.12, 80.48, 58.20,
55.15, 52.08, 50.97, 41.51, 31.72, 27.92, 24.19. MS (ES, positive
mode): 436.2 (M+ + Na). Anal. Calcd for C20H28ClNO6: C,
58.04; H, 6.82; Cl 8.57; N, 3.38. Found: C, 58.00; H, 6.61; Cl,
8.29; N, 3.29.
N-(p -Met h oxyb en zyl)-N-ch lor oa cet yl-Gly-Ot Bu (7f).
Yield: 85%. Eluent: EtOAc/hexane (1:8). HPLC: tR ) 10.94
min (A:B ) 41:59). 1H NMR (300 MHz, CDCl3): rotamers ratio
(1.4:1) δ major rotamer 7.13-6.78 (m, 4H), 4.55 (m, 2H), 4.14
(m, 2H), 3.85 (m, 2H), 3.74 (s, 3H), 1.39 (s, 9H). 13C NMR (75
MHz, CDCl3): major rotamer δ 167.50, 166.90, 159.22, 128.31,
126.81, 114.15, 81.74, 55.06, 51.64, 49.51, 40.90, 27.76. MS
N-(p-Meth oxyben zyl)-N-chlor oacetyl-L-Or n(Z)-OBzl(7m)-
Yield: 99%. Eluent: EtOAc/hexane (2:1). HPLC: tR ) 13.72
min (A:B ) 50:50). [R]D ) -39.1 (c ) 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): rotamers ratio (5:1) δ major rotamer 7.24-
6.66 (m, 14H), 5.19 (br s, 1H), 4.97 (m, 4H), 4.51 (d, 1H, J )
17.0), 4.33 (d, 1H, J ) 17.0), 4.20 (m, 1H), 3.94 (m, 2H), 3.66
(s, 3H), 3.00 (m, 2H), 1.97 (m, 1H), 1.71 (m, 1H), 1.42 (m 2H).
13C NMR (75 MHz, CDCl3): major rotamer δ 169.98, 167.25,
159.34, 156.29, 135.24, 129.49, 128.42, 128.26, 127.15, 127.10,
114.16, 67.10, 58.96, 55.18, 51.26, 41.46, 40.39, 30.57, 26.28.
(ES, positive mode): 328.1 (M+ + 1). Anal. Calcd for C16H22
ClNO4: C, 58.62; H, 6.76; Cl, 10.82; N, 4.27. Found: C, 58.66;
H, 6.54; Cl, 10.74; N, 4.15.
-
N-(p -Met h oxyb en zyl)-N-ch lor oa cet yl-Gly-OMe (7g).
Yield: 99%. Eluent: EtOAc/hexane (1:1). HPLC: tR ) 6.43 min
(A:B ) 30:70). 1H NMR (300 MHz, CDCl3): rotamers ratio (2.3:
1) δ major rotamer 7.06-6.80 (m, 4H), 4.50 (m, 2H), 4.13 (s,
2H), 3.92 (s, 2H), 3.70 (s, 3H), 3.60 (s, 3H). 13C NMR (75 MHz,
CDCl3): major rotamer δ 169.02, 167.34, 159.36, 128.40,
126.55, 114.26, 55.15, 52.08, 51.82, 46.64, 40.85. MS (ES,
positive mode): 286.2 (M+ + 1). Anal. Calcd for C13H16ClNO4:
C, 54.65; H, 5.64; Cl, 12.41; N, 4.90. Found: C, 54.38; H, 5.31;
Cl, 12.39; N, 4.85.
N-Ben zyl-N-ch lor oa cetyl-L-Ala -OtBu (7h ). Yield: 99%.
Eluent: gradient from 3 to 30% of EtOAc in hexane. HPLC:
tR ) 5.60 min (A:B ) 50:50). [R]D ) -54.2 (c ) 1.13, CHCl3).
1H NMR (300 MHz, CDCl3): rotamers ratio (3.5:1) δ major
rotamer 7.39-7.20 (m, 5H), 4.71 (d, 1H, J ) 17.6), 4.54 (d,
1H, J ) 17.6), 4.47 (m, 1H), 4.08 (m, 2H), 1.44 (s, 9H), 1.34 (d,
1H, J ) 8.7). 13C NMR (75 MHz, CDCl3): major rotamer δ
170.04, 167.17, 136.37, 128.89, 127.80, 126.33, 81.75, 55.69,
50.64, 41.39, 27.85, 14.40. MS (ES, positive mode): 334.2 (M+
+ Na). Anal. Calcd for C16H22ClNO3: C, 61.63; H, 7.11; Cl,
11.37; N, 4.49. Found: C, 61.62; H, 6.95; Cl, 11.09; N, 4.18.
N-Ben zyl-N-ch lor oa cetyl-L-Ala -OMe (7i). Yield: 90%.
Eluent: gradient from 8 to 15% of EtOAc in hexane. HPLC:
tR ) 9.24 min (A:B ) 30:70). [R]D ) -49.7 (c ) 1.28, CHCl3).
1H NMR (200 MHz, CDCl3): rotamers ratio (6:1) δ major
rotamer 7.41-7.23 (m, 5H), 4.65 (m, 3H), 4.04 (m, 2H), 3.69
(s, 3H), 1.40 (d, 3H, J ) 7.2). 13C NMR (75 MHz, CDCl3): major
rotamer δ 171.51, 167.21, 136.30, 129.02, 127.97, 126.66, 55.08,
52.30, 50.85, 41.82, 14.51. MS (ES, positive mode): 270.2 (M+
+ 1). Anal. Calcd for C13H16ClNO3: C, 57.89; H, 5.98; Cl, 13.14;
N, 5.19. Found: C, 57.67; H, 5.77; Cl, 12.80; N, 4.85.
MS (ES, positive mode): 553.3 (M+ + 1). Anal. Calcd for C30H33
-
ClN2O6: C, 65.15; H, 6.01; Cl, 6.41; N, 5.07. Found: C, 64.88;
H, 5.98; Cl, 6.44; N, 4.76.
Gen er a l P r oced u r es for th e Syn th esis of 2-a zetid in on e
Der iva tives 8. Cycliza tion P r om oted by Na H. A solution
of the corresponding N-benzyl-N-chloroacetyl derivative 7 (0.7
mmol) in dry CH3CN (5 mL) was treated with NaH (36 mg,
1.5 mmol) and stirred at room temperature until disappear-
ance of the starting material (see Table 1). The reaction
mixture was acidified to pH 3 and evaporated. The resulting
residue was partitioned between EtOAc and H2O, and the
phases were separated. The organic layer was dried over Na2-
SO4 and evaporated, leaving a residue which was purified on
a silica gel column, using the solvent system specified in each
case.
Cycliza tion P r om oted by Cs2CO3. A solution of the
corresponding N-benzyl-N-chloroacetyl derivative 7 (1.6 mmol)
in dry CH3CN or DMF (20 mL) was treated with Cs2CO3 (1.04
g, 3.2 mmol) and stirred at room temperature until disappear-
ance of the starting material (see Table 1). After evaporation
of the solvent, the residue was partitioned between EtOAc and
H2O, and the phases were separated. The workup was
continued as above.
1,4-Diben zyl-4-ter t-bu toxyca r bon yl-2-a zetid in on e (Bzl-
R-Bzl-Azn -OtBu , 8a ). Eluent: gradient from 15 to 50% of
EtOAc in hexane. HPLC: tR ) 10.80 min (A:B ) 50:50). 1H
NMR (300 MHz, CDCl3): δ 7.35-7.01 (m, 10H), 4.56 (d, 1H,
J ) 15.5), 4.38 (d, 1H, J ) 15.5), 3.32 (d, 1H, J ) 14.5), 3.23
(d, 1H, J ) 14.0), 2.94 (d, 1H, J ) 14.5), 2.89 (d, 1H, J ) 14.0),
1.30 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 169.53, 166.72,
136.83, 134.90, 129.58, 128.57, 128.42, 128.31, 127.51, 127.11,
82.77, 63.83, 45.65, 44.78, 39.97, 27.63. MS (ES, positive
mode): 352.2 (M+ + 1). Anal. Calcd for C22H25NO3: C, 75.19;
H, 7.17; N, 3.99. Found: C, 75.02; H, 7.33; N, 3.76.
1,4-Diben zyl-4-m eth oxyca r bon yl-2-a zetid in on e (Bzl-R-
Bzl-Azn -OMe, 8b). Eluent: EtOAc/hexane (1:3). HPLC: tR
) 6.44 min (A:B ) 45:55). 1H NMR (300 MHz, CDCl3): δ 7.35-
N-(p-Meth oxyben zyl)-N-ch lor oa cetyl-L-Leu -OtBu (7j).
Yield: 73%. Eluent: EtOAc/hexane (1:10). HPLC: tR ) 8.18
min (A:B ) 41:59). [R]D ) -59.9 (c ) 1.59, CHCl3). H NMR
(300 MHz, CDCl3): rotamers ratio (2.8:1) δ major rotamer
7.19-6.86 (m, 4H), 4.65 (d, 1H, J ) 17.0), 4.43 (d, 1H, J )
17.0), 4.23 (m, 1H), 3.98 (s, 2H), 3.78 (s, 3H), 1.84 (m, 1H),
1.51 (m, 2H), 1.40 (s, 9H), 0.87 (d, 3H, J ) 6.3), 0.77 (d, 3H, J
) 6.3). 13C NMR (75 MHz, CDCl3): major rotamer δ 169.95,
167.29, 159.16, 128.19, 127.93, 114.14, 81.59, 57.79, 55.21,
50.13, 41.68, 38.35, 27.81, 25.19, 22.36, 22.25. MS (ES, positive
1

3544 J . Org. Chem., Vol. 66, No. 10, 2001
Gerona-Navarro et al.
7.01 (m, 10H), 4.51 (d, 1H, J ) 15.4), 4.41 (d, 1H, J ) 15.4),
3.45 (s, 3H), 3.29 (d, 1H, J ) 14.8), 3.28 (d, 1H, J ) 14.0), 2.97
(d, 1H, J ) 14.0), 2.96 (d, 1H, J ) 14.8). 13C NMR (75 MHz,
CDCl3): δ 170.91, 166.17, 136.03, 134.43, 129,45, 128.46,
128.43, 128.35, 127.47, 127.13, 62.78, 52.08, 45.24, 44.76,
39.35. MS (ES, positive mode): 310.3 (M+ + 1). Anal. Calcd
for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.81;
H, 6.11; N, 4.54.
4-Ben zyl-1-(p-m eth oxyben zyl)-4-ter t-bu toxyca r bon yl-
2-a zetid in on e (P m b-R-Bzl-Azn -OtBu , 8c). Eluent: gradient
from 20 to 30% of EtOAc in hexane. HPLC: tR ) 9.67 min
(A:B ) 50:50). 1H NMR (200 MHz, CDCl3): δ 7.28-6.85 (m,
9H), 4.54 (d, 1H, J ) 15.4), 4.29 (d, 1H, J ) 15.4), 3.79 (s,
3H), 3.27 (d, 1H, J ) 14.6), 3.21 (d, 1H, J ) 13.9), 2.91 (d, 1H,
J ) 14.6), 2.83 (d, 1H, J ) 13.9), 1.32 (s, 9H). 13C NMR (50
MHz, CDCl3): δ 169.56, 166.66, 159.01, 134.94, 129.70, 128.59,
128.86, 128.41, 127.10, 113.92, 82.75, 63.78, 55.23, 45.55,
44.20, 40.01, 27.67. MS (ES, positive mode): 382.2 (M+ + 1).
Anal. Calcd for C23H27NO4: C, 72.42; H, 7.13; N, 3.67. Found:
C, 72.44; H, 7.30; N, 3.88.
4-Ben zyl-1-(p -m et h oxyb en zyl)-4-m et h oxyca r b on yl-2-
a zetid in on e (P m b-R-Bzl-Azn -OMe, 8d ). Eluent: EtOAc/
hexane (1:5). HPLC: tR ) 5.70 min (A:B ) 45:55). 1H NMR
(300 MHz, CDCl3): δ 7.25-6.82 (m, 9H), 4.38 (m, 2H), 3.74
(s, 3H), 3.47 (s, 3H), 3.24 (d, 1H, J ) 14.0), 3.22 (d, 1H, J )
14.7), 2.92 (d, 1H, J ) 14.0), 2.89 (d, 1H, J ) 14.7). 13C NMR
(75 MHz, CDCl3): δ 170.85, 165.85, 158.75, 134.42, 129.61,
129.35, 128.29, 127.98, 126.95, 113.58, 62.52, 54.90, 51.97,
45.03, 44.19, 39.37. MS (ES, positive mode): 340.1 (M+ + 1),
362.2 (M+ + Na). Anal. Calcd for C20H21NO4: C, 70.78; H, 6.24;
N, 4.13. Found: C, 70.54; H, 6.26; N, 4.17.
4-Ben zyl-1-(p-m eth oxyben zyl)-4-ben zyloxyca r bon yl-2-
a zetid in on e (P m b-R-Bzl-Azn -OBzl, 8e). Eluent: EtOAc/
hexane (1:4). HPLC: tR ) 9.21 min (A:B ) 50:50). 1H NMR
(300 MHz, CDCl3): δ 7.29-6.75 (m, 14H), 4.88 (s, 2H), 4.38
(d, 1H, J ) 15.3), 4.27 (d, 1H, J ) 15.3), 3.71 (s, 3H), 3.24 (d,
1H, J ) 14.7), 3.19 (d, 1H, J ) 14.0), 2.88 (d, 1H, J ) 14.7),
2.85 (d, 1H, J ) 14.0). 13C NMR (75 MHz, CDCl3): δ 170.44,
166.14, 158.97, 134.68, 134.53, 129.81, 129.52, 128.53, 128.50,
128.37, 128.19, 127.15, 113.83, 67.28, 63.01, 55.14, 45.37,
44.29, 39.69. MS (ES, positive mode): 438.1 (M+ + Na). Anal.
Calcd for C26H25NO4: C, 75.16; H, 6.06; N, 3.37. Found: C,
74.97; H, 5.89; N, 3.15.
1-Ben zyl-4-m et h oxyca r b on yl-4-m et h yl-2-a zet id in on e
(Bzl-R-Me-Azn -OMe, 8i). Eluent: EtOAc/hexane (1:4).
HPLC: tR ) 5.44 min (A:B ) 30:70). 1H NMR (300 MHz,
CDCl3): δ 7.27 (m, 5H), 4.47 (d, 1H, J ) 15.2), 4.32 (d, 1H, J
) 15.2), 3.54 (s, 3H), 3.24 (d, 1H, J ) 14.5), 2.81 (d, 1H, J )
14.5), 1.37 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 172.25,
165.60, 135.69, 128.54, 128.46, 127.59, 58.76, 52.23, 48.89,
44.63, 20.49. MS (ES, positive mode): 234.2 (M+ + 1). Anal.
Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C,
66.73; H, 6.67; N, 5.81.
1-(p-Meth oxyben zyl)-4-ter t-bu toxyca r bon yl-4-isobu tyl-
2-a zetid in on e (P m b-R-iBu -Azn -OtBu , 8j). Eluent: EtOAc/
hexane (1:7). HPLC: tR ) 7.04 min (A:B ) 55:45). 1H NMR
(300 MHz, CDCl3): δ 7.14-6.76 (m, 4H), 4.39 (d, 1H, J ) 15.5),
4.19 (d, 1H, J ) 15.5), 3.71 (s, 3H), 3.33 (d, 1H, J ) 14.8), 2.74
(d, 1H, J ) 14.8), 1.92 (dd, 1H, J ) 13.4, 5.1), 1.48 (m, 1H),
1.31 (s, 9H), 1.19 (dd, 1H, J ) 13.4, 8.8), 0.77 (d, 6H, J ) 6.7).
13C NMR (75 MHz, CDCl3): δ 169.81, 166.91, 158.78, 129.17,
113.72, 82.35, 63.37, 55.10, 46.14, 43.43, 42.91, 27.64, 25.15,
23.79, 22.30. MS (ES, positive mode): 370.4 (M+ + Na). Anal.
Calcd for C20H29NO4: C, 69.14; H, 8.41; N, 4.03. Found: C,
68.98; H, 8.20; N, 4.20.
1-(p-Meth oxyben zyl)-4-m eth oxyca r bon yl-4-isobu tyl-2-
a zetid in on e (P m b-R-iBu -Azn -OMe, 8k ). Eluent: EtOAc/
hexane (1:4). HPLC: tR ) 7.81 min (A:B ) 40:60). 1H NMR
(300 MHz, CDCl3): δ 7.10-6.73 (m, 4H), 4.26 (m, 2H), 3.68
(s, 3H), 3.43 (s, 3H), 3.34 (d, 1H, J ) 14.6), 2.77 (d, 1H, J )
14.6), 1.95 (dd, 1H, J ) 13.7, 5.1), 1.46 (m, 1H), 1.25 (dd, 1H,
J ) 13.7, 8.5), 0.73 (d, 6H, J ) 6.6). 13C NMR (75 MHz,
CDCl3): δ 171.25, 166.51, 158.76, 129.31, 128.62, 113.68, 62.38,
55.09, 52.04, 46.15, 43.51, 42.44, 25.03, 23.58, 22.38. MS (ES,
positive mode): 306.3 (M+ + 1). Anal. Calcd for C17H23NO4:
C, 66.86; H, 7.59; N, 4.59. Found: C, 66.91; H, 7.52; N, 4.60.
1-(p-Meth oxyben zyl)-4-m eth oxyca r bon yl-4-(2-ter t-bu -
t oxyca r bon yl)et h yl-2-a zet id in on e (8l). Eluent: EtOAc/
hexane (1:4). HPLC: tR ) 8.04 min (A:B ) 41:59). 1H NMR
(300 MHz, CDCl3): δ 7.21-6.83 (m, 4H), 4.43 (d, 1H, J ) 16.0),
4.29 (d, 1H, J ) 16.0), 3.78 (s, 3H), 3.58 (s, 3H), 3.22 (d, 1H,
J ) 15.0), 2.84 (d, 1H, J ) 15.0), 2.15 (m, 2H), 1.98 (m, 2H),
1.39 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 171.50, 171.28,
165.80, 159.09, 129.96, 127.79, 113.93, 80.79, 61.68, 55.17,
52.46, 45.55, 44.23, 29.88, 28.28, 27.93. MS (ES, positive
mode): 400.4 (M+ + Na). Anal. Calcd for C20H27NO6: C, 63.65;
H, 7.21; N, 3.71. Found: C, 63.47; H, 6.97; N, 3.63.
1-(p-Meth oxyben zyl)-4-ter t-bu toxyca r bon yl-2-a zetid i-
n on e (P m b-Azn -OtBu , 8f). Eluent: EtOAc/hexane (1:6).
HPLC: tR ) 7.12 min (A:B ) 41:59). 1H NMR (200 MHz,
CDCl3): δ 7.19-6.90 (m, 4H), 4.56 (d, 1H, J ) 14.8), 4.09 (d,
1H, J ) 14.8), 3.86 (dd, 1H, J ) 5.6, 2.4), 3.77 (s, 3H), 3.15
(dd, 1H, J ) 14.3, 5.6), 2.86 (dd, 1H, J ) 14.3, 2.4), 1.41 (s,
9H). 13C NMR (75 MHz, CDCl3): δ 169.45, 165.81, 159.14,
129.78, 126.86, 114.07, 82.39, 55.17, 50.45, 44.80, 41.50, 27.83.
MS (ES, positive mode): 314.3 (M+ + Na). Anal. Calcd for
1-(p-Meth oxyben zyl)-4-ben zyloxyca r bon yl-4-[3-(ben zy-
loxyca r bon yl)a m in o]p r op yl-2-a zetid in on e (8m ). Eluent:
1
EtOAc/hexane (1:1). HPLC: tR ) 6.79 min (A:B ) 50:50). H
NMR (300 MHz, CDCl3): δ 7.24-6.69 (m, 14H), 4.97 (m, 3H),
4.94 (s, 2H), 4.38 (d, 1H, J ) 15.3), 4.06 (d, 1H, J ) 15.3), 3.63
(s, 3H), 3.11 (d, 1H, J ) 14.6), 2.85 (m, 2H), 1.84 (m, 1H), 1.48
(m, 1H), 1.16 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 171.08,
165.86, 159.10, 156.16, 136.45, 134.89, 129.82, 128.63, 128.57,
128.43, 128.29, 128.06, 128.01, 113.90, 67.22, 66.52, 62.27,
55.12, 45.56, 44.22, 40.39, 30.57, 24.28. MS (ES, positive
mode): 517.0 (M+ + 1). Anal. Calcd for C30H32N2O6: C, 69.75;
H, 6.24; N, 5.42. Found: C, 70.01; H, 6.18; N, 5.33.
C
16H21NO4: C, 65.96; H, 7.26; N, 4.81. Found: C, 66.01; H,
7.12; N, 5.11.
1-(p-Meth oxyben zyl)-4-m eth oxyca r bon yl-2-a zetid in o-
n e (P m b-Azn -OMe, 8g). Eluent: EtOAc/hexane (1:1).
HPLC: tR ) 3.79 min (A:B ) 30:70). 1H NMR (300 MHz,
CDCl3): δ 7.05-6.75 (m, 4H), 4.56 (d, 1H, J ) 14.8), 4.01 (d,
1H, J ) 14.8), 3.82 (dd, 1H, J ) 5.6, 2.6), 3.69 (s, 3H), 3.59 (s,
3H), 3.07 (dd, 1H, J ) 14.5, 5.6), 2.90 (dd, 1H, J ) 14.5, 2.6).
13C NMR (75 MHz, CDCl3): δ 170.72, 165.47, 159.12, 129.74,
126.63, 114.00, 55.11, 52.23, 49.54, 44.87, 41.59. MS (ES,
positive mode): 250.2 (M+ + 1). Anal. Calcd for C13H15NO4:
C, 62.64; H, 6.07; N, 5.62. Found: C, 62.50; H, 6.11; N, 5.55.
1-Ben zyl-4-ter t-bu toxyca r bon yl-4-m eth yl-2-a zetid in o-
n e (Bzl-R-Me-Azn -OtBu , 8h ). Eluent: gradient from 20 to
50% of EtOAc in hexane. HPLC: tR ) 4.24 min (A:B ) 50:50).
1H NMR (300 MHz, CDCl3): δ 7.29 (m, 5H), 4.57 (d, 1H, J )
15.3), 4.26 (d, 1H, J ) 15.3), 3.21 (d, 1H, J ) 14.4), 2.79 (d,
1H, J ) 14.4), 1.38 (s, 9H), 1.31 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 171.04, 166.08, 136.21, 128.55, 128.51, 127.59, 82.29,
59.67, 48.79, 44.61, 27.71, 20.80. MS (ES, positive mode): 276.2
(M+ + 1). Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N,
5.09. Found: C, 69.54; H, 7.55; N, 4.91.
3-Ben zyl-4-(p -m et h oxyb en zyl)-2,5-d ioxop er h yd r oox-
a zin e (9d ). HPLC: tR ) 3.94 min (A:B ) 45:55). [R]D ) -3.9
(c ) 0.26, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.29-6.82
(m, 9H), 5.26 (d, 1H, J ) 14.6), 4.27 (m, 1H), 4.22 (d, 1H, J )
16.1), 3.83 (d, 1H, J ) 14.6), 3.75 (s, 3H), 3.12 (m, 2H), 3.05
(d, 1H, J ) 16.1). 13C NMR (75 MHz, CDCl3): δ 166.79, 163.52,
159.76, 134.02, 130.04, 129.74, 129.31, 128.33, 126.36, 114.54,
66.60, 58.25, 55.34, 46.39, 36.90. MS (ES, positive mode): 326.3
(M+ + 1), 348.2 (M+ + Na). Anal. Calcd for C19H19NO4: C,
70.14; H, 5.89; N, 4.30. Found: C, 69.89; H, 5.73; N, 4.22.
4-(p -m et h oxyb en zyl)-2,5-d ioxop er h yd r ooxa zin e (9f).
HPLC: tR ) 2.75 min (A:B ) 30:70). 1H NMR (300 MHz,
CDCl3): δ 7.17-6.86 (m, 4H), 4.78 (s, 2H), 4.52 (s, 2H), 3.97
(s, 2H), 3.78 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 164.67,
163.09, 159.66, 129.86, 126.19, 114.41, 67.54, 55.26, 48.64,
46.46. MS (ES, positive mode): 236.2 (M+ + 1), 258.2 (M+
+
Na). Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95.
Found: C, 61.15; H, 5.49; N, 5.78.

Synthesis of 4-Alkyl-4-carboxy-2-azetidinones
J . Org. Chem., Vol. 66, No. 10, 2001 3545
4-(p-Meth oxyben zyl)-3-isobu tyl-2,5-d ioxop er h yd r oox-
a zin e (9j). HPLC: tR ) 2.46 min (A:B ) 55:45). [R]D ) +17.3
(c ) 0.88, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.17-6.87
(m, 4H), 5.13 (d, 1H, J ) 14.7), 4.86 (d, 1H, J ) 16.1), 4.76 (d,
1H, J ) 16.1), 3.98 (d, 1H, J ) 14.7), 3.97 (m, 1H), 3.80 (s,
3H), 1.73 (m, 2H), 1.53 (m, 1H), 0.93 (d, 6H, J ) 6.3). 13C NMR
(75 MHz, CDCl3): δ 166.70, 163.80, 159.93, 130.05, 126,91,
114.73, 67.50, 55.68, 55.56, 47.28, 40.33, 24.74, 23.26, 21.73.
MS (ES, positive mode): 314.2 (M+ + Na). Anal. Calcd for
242.1 (M+ + Na). Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98;
N, 6.39. Found: C, 65.35; H, 6.21; N, 6.20.
1-(p -Met h oxyb en zyl)-4-ca r b oxy-4-isob u t yl-2-a zet id i-
n on e (P m b-R-iBu -Azn -OH, 10k ). Yield: 91% (from 8k ,
method B). Eluent: CH2Cl2/MeOH (50:1). HPLC: tR ) 3.04
1
min (A:B ) 40:60). H NMR (300 MHz, CDCl3): δ 10.08 (br s,
1H), 7.16-6.75 (m, 4H), 4.51 (d, 1H, J ) 15.4), 4.18 (d, 1H, J
) 15.4), 3.69 (s, 3H), 3.36 (d, 1H, J ) 15.0), 2.84 (d, 1H, J )
15.0), 1.90 (dd, 1H, J ) 13.7, 4.6), 1.52 (m, 1H), 1.24 (dd, 1H,
J ) 13.7, 8.9), 0.75 (d, 6H, J ) 6.5). 13C NMR (75 MHz,
CDCl3): δ 174.40, 167.89, 158.91, 129.62, 128.41, 113.78, 63.32,
55.14, 45.93, 44.13, 42.63, 25.07, 23.79, 22.31. MS (ES, positive
mode): 292.2 (M+ + 1). Anal. Calcd for C16H21NO4: C, 65.96;
H, 7.26; N, 4.81. Found: C, 66.01; H, 7.37; N, 4.69.
C
16H21NO4: C, 65.96; H, 7.26; N, 4.81. Found: C, 65.97; H,
7.20; N, 4.61.
Rem ova l of C-ter m in a l a lk yl gr ou p s fr om com p ou n d s
8. Meth od A. A solution of the corresponding 4-tert-butoxy-
carbonyl derivative (1.42 mmol) and TFA (1 mL) in CH2Cl2 (2
mL) was stirred at room temperature for 2 h, and the solvents
were evaporated to dryness. The resulting residue was purified
on a silica gel column, as specified.
Meth od B. A solution of the corresponding 4-methoxycar-
bonyl derivative (0.24 mmol) in MeOH (3 mL) was treated with
2 N NaOH (0.18 mL, 0.36 mmol), and the mixture was stirred
overnight at room temperature. After evaporation of the MeOH
the remaining aqueous mixture was diluted with H2O (5 mL),
acidified with 1 N HCl to pH 3, and extracted with EtOAc.
The extract was dried (Na2SO4) and evaporated. The resulting
residue was purified on a silica gel column, as specified.
Meth od C. A solution of the corresponding 4-benzyloxy-
carbonyl derivative (0.2 mmol) in EtOAc (17 mL) was hydro-
genated at room temperature and 15 psi of pressure for 7 h,
using 10% Pd-C as catalyst. After filtration of the catalyst,
the solvent was evaporated, and the resulting residue was
purified on a silica gel column, as specified.
4-Ca r boxy-1,4-d iben zyl-2-a zetid in on e (Bzl-R-Bzl-Azn -
OH, 10a ). Yield: 91% (from 8a , method A), 89% (from 8b,
method B). Eluent: CH2Cl2/MeOH (50:1). HPLC: tR ) 11.79
min (A:B ) 30:70). 1H NMR (300 MHz, DMSO-d6): δ 7.32-
7.10 (m, 10H), 4.48 (d, 1H, J ) 15.8), 4.26 (d, 1H, J ) 15.8),
3.20 (d, 1H, J ) 13.8), 3.09 (d, 1H, J ) 14.4), 3.04 (d, 1H, J )
13.8), 2.93 (d, 1H, J ) 14.4). 13C NMR (75 MHz, DMSO-d6): δ
172.34, 165.99, 137.07, 135.39, 129.86, 128.32, 128.28, 127.99,
127.17, 126.87, 62.66, 44.59, 44.49, 38.46. MS (ES, positive
mode): 296.2 (M+ + 1). Anal. Calcd for C18H17NO3: C, 73.20;
H, 5.80; N, 4.74. Found: C, 73.01; H, 6.13; N, 4.56.
Rem ova l of N-1 P r otectin g Gr ou p s fr om Com p ou n d s
8. Meth od A. Compound 10a (0.36 g, 1.2 mmol) was added to
a solution of Li (0.1 g, 14.6 mmol) in liquid NH3 (21 mL), THF
t
(6 mL), and BuOH (0.6 mL), at -78 °C. After 5 min of reaction
at -78 °C, the solvents were evaporated, and the resulting
residue was dissolved in H2O and acidified to pH 3. The
aqueous layer was extracted with EtOAc, and the organic
extract was washed with NaHCO3 and brine, dried over Na2-
SO4, and evaporated. The resulting residue was purified on a
silica gel column, using CH2Cl2/MeOH (30:1) as eluent.
Meth od B. A solution of the corresponding 1-(p-methoxy-
benzyl)-2-azetidinone (0.98 mmol) in CH3CN/H2O (1:1, 30 mL)
was treated with K2HPO4 (8.4 mmol) and K2S2O8 (10.9 mmol),
and heated to 75 °C, under Ar atmosphere, for 3-5 h. After
evaporation of the CH3CN, the aqueous layer was extracted
with EtOAc, and the organic extract was washed with NaHCO3
and brine, dried over Na2SO4, and evaporated. The resulting
residue was purified on a silica gel column, as specified.
4-Ben zyl-4-ca r b oxy-2-a zet id in on e (H -R-Bzl-Azn -OH ,
11a ). Yield: 60% (from 10a , method A). HPLC: tR ) 12.14
1
min (A:B ) 10:90). H NMR (300 MHz, CDCl3): δ 7.53 (br s,
1H), 7.18 (m, 5H), 6.81 (br s, 1H), 3.32 (d, 1H, J ) 13.9), 3.07
(d, 1H, J ) 14.9), 2.92 (d, 1H, J ) 13.9), 2.85 (d, 1H, J ) 14.9).
13C NMR (75 MHz, (CD3)2CO): δ 174.00, 165.50, 137.00,
130.18, 128.48, 127.10, 59.83, 39.71, 38.51. MS (ES, positive
mode): 206.1 (M+ + 1), 228.1 (M+ + Na). Anal. Calcd for
C
11H11NO3: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.11; H,
5.81; N, 6.65. This compound was also obtained (87%) from
11c, upon treatment with TFA.
4-Ben zyl-1-(p-m eth oxyben zyl)-4-ca r boxy-2-a zetid in o-
n e (P m b-R-Bzl-Azn -OH, 10c). Yield: 85% (from 8c, method
A), 87% (from 8d , method B), 92% (from 8e, method C).Elu-
ent: CH2Cl2/MeOH (50:1). HPLC: tR ) 6.03 min (A:B ) 35:
4-Ben zyl-4-ter t-b u t oxyca r b on yl-2-a zet id in on e (H -R-
Bzl-Azn -OtBu , 11c). Yield: 65% (from 8c, method B). Elu-
ent: gradient from 10 to 25% of EtOAc in hexane. HPLC: tR
) 2.79 min (A:B ) 50:50). 1H NMR (300 MHz, CDCl3): δ 7.32-
6.80 (m, 5H), 6.35 (br s, 1H), 3.34 (d, 1H, J ) 13.7), 3.05 (dd,
1H, J ) 14.9, 2.6), 2.91 (d, 1H, J ) 13.7), 2.89 (d, 1H, J )
14.9), 1.33 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 170.83,
166.18, 135.18, 129.44, 128.50, 127.29, 82.73, 59.13, 47.65,
42.34, 27.74. MS (ES, positive mode): 262.1 (M+ + 1), 284.2
(M+ + Na). Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N,
5.36. Found: C, 68.75; H, 7.08; N, 5.24.
1
65). H NMR (300 MHz, CDCl3): δ 8.40 (br s, 1H), 7.22-6.76
(m, 9H), 4.51 (d, 1H, J ) 15.4), 4.22 (d, 1H, J ) 15.4), 3.70 (s,
3H), 3.19 (d, 1H, J ) 14.8), 3.15 (d, 1H, J ) 14.0), 2.87 (d, 1H,
J ) 14.8), 2.83 (d, 1H, J ) 14.0). 13C NMR (75 MHz, CDCl3):
δ 174.43, 167.17, 159.11, 134.45, 130.13, 129.67, 128.57,
128.05, 127.27, 113.91, 63.39, 55.21, 45.13, 44.83, 39.52. MS
(ES, positive mode): 326.2 (M+ + 1). Anal. Calcd for C19H19
-
NO4: C, 70.14; H, 5.89; N, 4.30. Found: C, 70.02; H, 6.09; N,
4.34.
4-Ben zyl-4-m et h oxyca r bon yl-2-a zet id in on e (H-R-Bzl-
Azn -OMe, 11d ). Yield: 67% (from 8d , method B). Eluent:
gradient from 25 to 50% of EtOAc in hexane. HPLC: tR ) 2.20
1-(p-Met h oxyben zyl)-4-ca r b oxy-2-a zet id in on e (P m b-
Azn -OH, 10g). Yield: 89% (from 8g, method B). Eluent: CH2-
Cl2/MeOH (50:1). HPLC: tR ) 2.05 min (A:B ) 30:70). 1H NMR
(300 MHz, CDCl3): δ 7.10-6.80 (m, 4H), 6.41 (br s, 1H), 4.69
(d, 1H, J ) 14.8), 4.02 (d, 1H, J ) 14.8), 3.87 (dd, 1H, J ) 5.6,
2.2), 3.73 (s, 3H), 3.16 (dd, 1H, J ) 14.6, 5.6), 3.00 (dd, 1H, J
) 14.6, 2.2). 13C NMR (75 MHz, CDCl3): δ 174.23, 166.23,
159.32, 129.96, 126.45, 114.23, 55.26, 49.46, 45.07, 41.58. MS
1
min (A:B ) 40:60). H NMR (300 MHz, CDCl3): δ 7.27-7.05
(m, 5H), 6.28 (br s, 1H), 3.66 (s, 3H), 3.38 (d, 1H, J ) 13.7),
3.12 (dd, 1H, J ) 14.9, 2.5), 2.95 (dd, 1H, J ) 14.9, 0.8), 2.94
(d, 1H, J ) 13.7). 13C NMR (75 MHz, CDCl3): δ 172.24, 165.58,
134.91, 129.32, 128.71, 127.47, 58.93, 52.64, 47.72, 42.45. MS
(ES, positive mode): 220.1 (M+ + 1). Anal. Calcd for C12H13
-
NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.82; H, 6.10; N,
6.10. This compound was also obtained by treatment of
compound 11a with diazomethane.
(ES, positive mode): 236.2 (M+ + 1). Anal. Calcd for C12H13
-
NO4: C, 61.27; H, 5.57; N, 5.95. Found: C, 61.02; H, 5.60; N,
5.85.
Syn th esis of d ip ep tid e d er iva tives. Gen er a l P r oce-
d u r e. A solution of the corresponding 4-carboxy derivative 10
(0.33 mmol) and H-L-Ala-OMe or H-L-Phe-OMe (0.66 mmol)
in dry THF (4 mL) was successively treated with BOP (0.29
g, 0.66 mmol) and TEA (0.18 mL, 1.32 mmol) at room
temperature. The stirring was continued until complete disap-
pearance of the starting material 10 (1-2 days). The isomers
ratio was determined by HPLC on the crude reaction mixtures.
To characterize the obtained dipeptide derivatives, the solvent
1-Ben zyl-4-ca r boxy-4-m eth yl-2-a zetid in on e (Bzl-R-Me-
Azn -OH, 10h ). Yield: 99% (from 8h , method A). Eluent: CH2-
Cl2/MeOH (50:1). HPLC: tR ) 4.46 min (A:B ) 30:70). 1H NMR
(300 MHz, CDCl3): δ 8.15 (br s, 1H), 7.23 (m, 5H), 4.65 (d,
1H, J ) 15.1), 4.15 (d, 1H, J ) 15.1), 3.21 (d, 1H, J ) 14.6),
2.79 (d, 1H, J ) 14.6), 1.25 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 175.57, 166.82, 135.59, 128.65, 128.61, 127.81, 59.43,
48.67, 45.09, 20.79. MS (ES, positive mode): 220.1 (M+ + 1),

3546 J . Org. Chem., Vol. 66, No. 10, 2001
Gerona-Navarro et al.
was evaporated, and the residue was dissolved in EtOAc and
washed with citric acid (10%), NaHCO3 (10%), and brine. The
organic layer was dried (Na2SO4) and evaporated, leaving a
residue which was purified on a silica gel column as specified
in each case.
+ 1). Anal. Calcd for C22H24N2O4: C, 69.46; H, 6.36; N, 7.36.
Found: C, 69.40; H, 6.27; N, 7.09.
Bzl-R-iBu -Azn -L-P h e-OMe (12k and 13k ). Yield: 86%
(from 10k , and H-L-Phe-OMe), 12k :13k ) 71:29. EtOAc/
hexane (1:3). Isomer (R,S) 12k : HPLC: tR ) 65.55 min (A:B
1
Bzl-R-Bzl-Azn -L-Ala -OMe (12a and 13a ). Yield: 83% (from
10a , and H-L-Ala-OMe), 12a :13a ) 67:33. Eluent: EtOAc/
hexane (1:4). Isomer (R,S) 12a : HPLC: tR ) 19.11 min (A:B
) 25:75). [R]D ) -3.5 (c ) 1.03, CHCl3). H NMR (300 MHz,
CDCl3): δ 7.23-6.76 (m, 9H), 5.91 (d, 1H, J ) 7.9), 4.59 (m,
1H), 4.31 (d, 1H, J ) 15.4), 4.12 (d, 1H, J ) 15.4), 3.71 (s,
3H), 3.63 (s, 3H), 2.96 (dd, 1H, J ) 13.9, 5.5), 2.82 (d, 1H, J )
14.9), 2.69 (d, 1H, J ) 14.9), 2.60 (dd, 1H, J ) 13.9, 8.2), 1.85
(dd, 1H, J ) 14.0, 4.4), 1.51 (m, 1H), 1.47 (dd, 1H, J ) 14.0,
8.0), 0.78 (d, 3H, J ) 6.2), 0.73 (d, 3H, J ) 6.6). 13C NMR (75
MHz, CDCl3): δ 171.38, 171.08, 167.01, 159.32, 135.63, 130.05,
128.92, 128.66, 128.51, 127.24, 114.23, 63.95, 55.27, 52.99,
52.36, 47.26, 44.19, 41.69, 37.34, 24.57, 24.49, 22.75. MS (ES,
positive mode): 453.3 (M+ + 1). Anal. Calcd for C26H32N2O5:
C, 69.01; H, 7.13; N, 6.19. Found: C, 68.88; H, 6.15; N, 5.95.
Isomer (S,S) 13k : HPLC: tR ) 65.55 min (A:B ) 25:75). [R]D
) +27.3 (c ) 0.21, CHCl3). 1H NMR (300 MHz, CDCl3): δ
7.22-6.75 (m, 9H), 5.91 (d, 1H, J ) 7.0), 4.66 (m, 1H), 4.60
(m, 2H), 3.71 (s, 3H), 3.64 (s, 3H), 3.06 (d, 1H, J ) 14.8), 2.95
(dd, 1H, J ) 14.0, 6.2), 2.85 (d, 1H, J ) 14.8), 2.76 (dd, 1H, J
) 14.0, 6.8), 1.78 (dd, 1H, J ) 13.8, 4.4), 1.46 (m, 1H), 1.34
(dd, 1H, J ) 14.0, 6.8), 0.72 (d, 3H, J ) 6.8), 0.70 (d, 3H, J )
7.3). 13C NMR (75 MHz, CDCl3): δ 171.47, 170.56, 166.96,
159.20, 135.54, 129.75, 129.00, 128.68, 128.63, 127.29, 114.20,
63.84, 55.28, 52.97, 52.45, 46.86, 43.90, 42.32, 37.44, 24.73,
24.34, 22.69. MS (ES, positive mode): 453.3 (M+ + 1). Anal.
Calcd for C26H32N2O5: C, 69.01; H, 7.13; N, 6.19. Found: C,
68.97; H, 6.03; N, 5.90.
1
) 30:70). [R]D ) -32.9 (c ) 0.67, CHCl3). H NMR (300 MHz,
CDCl3): δ 7.34-7.15 (m, 10H), 5.78 (d, 1H, J ) 7.0), 4.68 (d,
1H, J ) 15.3), 4.28 (m, 1H), 4.11 (d, 1H, J ) 15.3), 3.70 (s,
3H), 3.39 (d, 1H, J ) 14.3), 3.22 (d, 1H, J ) 14.3), 3.03 (m,
2H), 0.93 (d, 3H, J ) 7.2). 13C NMR (50 MHz, CDCl3): δ 172.40,
171.07, 166.68, 136.73, 135.24, 130.06, 129.32, 129.11, 128.81,
128.21, 127.48, 64.72, 52.45, 48.09, 47.84, 45.39, 39.77, 16.95.
MS (ES, positive mode): 381.4 (M+ + 1), 403.3 (M+ + Na).
Anal. Calcd for C22H24N2O4: C, 69.46; H, 6.36; N, 7.36.
Found: C, 69.29; H, 6.19; N, 7.17. Isomer (S,S) 13a : HPLC:
tR ) 20.66 min (A:B ) 30:70). [R]D ) +46.7 (c ) 0.38, CHCl3).
1H NMR (300 MHz, CDCl3): δ 7.36-7.16 (m, 10H), 5.86 (d,
1H, J ) 7.2), 4.79 (d, 1H, J ) 15.2), 4.25 (m, 1H), 3.92 (d, 1H,
J ) 15.2), 3.65 (s, 3H), 3.56 (d, 1H, J ) 14.5), 3.27 (d, 1H, J )
14.5), 3.10 (d, 1H, J ) 14.8), 2.99 (d, 1H, J ) 14.8), 0.81 (d,
3H, J ) 7.2). 13C NMR (50 MHz, CDCl3): δ 172.39, 171.17,
167.10, 136.89, 135.50, 130.10, 129.35, 129.20, 128.92, 128.32,
127.54, 64.66, 52.45, 48.42, 47.90, 45.20, 38.66, 16.98. MS (ES,
positive mode): 381.4 (M+ + 1). Anal. Calcd for C22H24N2O4:
C, 69.46; H, 6.36; N, 7.36. Found: C, 69.35; H; 6.41; N, 7.16.
P m b-R-Bzl-Azn -L-Ala-OMe (12c and 13c).Yield: 89% (from
10c, and H-L-Ala-OMe), 12c:13c ) 67:33 or 65:35, see Table
2. Eluent: gradient from 6 to 12% of EtOAc in hexane. Isomer
(R,S) 12c: HPLC: tR ) 9.58 min (A:B ) 35:65). [R]D ) -20.6
(c ) 1.1, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.33-6.80 (m,
9H,), 5.87 (d, 1H, J ) 6.9), 4.62 (d, 1H, J ) 15.3), 4.29 (m,
1H), 4.04 (d, 1H, J ) 15.3), 3.76 (s, 3H), 3.61 (s, 3H), 3.37 (d,
1H, J ) 14.4), 3.21 (d, 1H, J ) 14.4), 3.00 (m, 2H), 0.97 (d,
3H, J ) 7.3). 13C NMR (75 MHz, CDCl3): δ 172.30, 171.12,
166.52, 159.46, 135.19, 130.42, 129.99, 129.62, 128.72, 128.56,
127.38, 114.32, 64.36, 55.28, 52.35, 48.25, 48.16, 44.91, 39.87,
17.15. MS (ES, positive mode): 433.1 (M+ + 1). Anal. Calcd
for C23H26N2O5: C, 67.30; H, 6.38; N, 6.82. Found: C, 67.50;
H, 6.06; N, 6.85. Isomer (S,S) 13c: HPLC: tR ) 10.28 min
(A:B ) 35:65). [R]D ) +30.5 (c ) 0.9, CHCl3). 1H NMR (300
MHz, CDCl3): δ 7.33-6.80 (m, 9H), 5.93 (d, 1H, J ) 7.3), 4.71
(d, 1H, J ) 15.1), 4.29 (m, 1H), 3.88 (d, 1H, J ) 15.1), 3.76 (s,
3H), 3.70 (s, 3H), 3.53 (d, 1H, J ) 14.5), 3.24 (d, 1H, J ) 14.5),
3.07 (d, 1H, J ) 15.0), 2.97 (d, 1H, J ) 15.0), 0.88 (d, 3H, J )
7.2). 13C NMR (75 MHz, CDCl3): δ 172.30, 171.12, 166.92,
159.51, 135.41, 130.42, 130.17, 129.72, 128.78, 128.44, 127.38,
114.51, 64.52, 55.27, 52.35, 48.59, 48.10, 44.69, 38.88, 17.15.
MS (ES, positive mode): 433.1 (M+ + 1). Anal. Calcd for
P m b-L-P h e-L-Ala -OMe (16). A solution of H-L-Phe-L-Ala-
OMe.CF3CO2H (0.93 g, 2.55 mmol) in MeOH (4 mL) was
treated with TEA (0.35 mL, 2.55 mmol) and p-methoxyben-
zaldehyde (0.46 mL, 3.83 mmol). After stirring at room
temperature for 1.5 h, the solution was cooled to 0 °C and
treated with NaBH4 (0.19 g, 5.1 mmol). The reaction was
allowed to warm to room temperature and stirred for 1 h. The
MeOH was evaporated and the residue extracted with EtOAc
and washed with H2O. The organic layer was dried (Na2SO4)
and evaporated, leaving a residue (0.52 g, 56%) which was used
in the next step without further purification. 1H NMR (300
MHz, CDCl3): δ 7.84 (d, 1H, J ) 8.1), 7.32-6.94 (m, 9H), 4.59
(m, 1H), 3.73 (s, 3H), 3.68 (s, 3H), 3.64 (d, 1H, J ) 12.7), 3.40
(d, 1H, J ) 12.7), 3.31 (dd, 1H, J ) 9.7, 3.9), 3.12 (dd, 1H, J )
13.9, 3.9), 2.63 (dd, 1H, J ) 13.9, 9.7), 1.67 (br s, 1H), 1.33 (d,
3H, J ) 7.2. MS (ES, positive mode): 271.2 (M+ + 1).
P m b-N-ch lor oa cetyl-L-P h e-L-Ala -OMe (17). A solution of
compound 16 (0.51 g, 1.37 mmol) in THF (10 mL) was treated
with propylene oxide (1.45 mL, 20.6 mmol) and chloroacetyl
chloride (0.13 mL, 1.65 mmol). After stirring at room temper-
ature for 1 h, the solvents were evaporated, and the resulting
residue was purified on a silica gel column, using EtOAc/
hexane (1:3), yielding 0.5 g (76%) of the title compound.
HPLC: tR ) 25.54 min (A:B ) 35:65). [R]D ) +8.05 (c ) 0.97,
CHCl3). 1H NMR (200 MHz, CDCl3): rotamers ratio (9:1) δ
major rotamer 7.35-6.80 (m, 9H), 6.72 (d, 1H, J ) 7.1), 4.84
(m, 1H), 4.60 (d, 1H, J ) 16.0), 4.45 (m, 1H), 4.22 (d, 1H, J )
16.0), 3.99 (m, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 3.24 (m 2H), 1.34
(d, 3H, J ) 7.2). 13C NMR (75 MHz, CDCl3): major rotamer δ
172.77, 166.77, 163.53, 159.73, 136.92, 134.00, 130.01, 129.72,
129.28, 128.30, 114.52, 58.24, 55.28, 53.26, 52.37, 46.36, 41.71,
36.86, 16.02. MS (ES, positive mode): 447.1 (M+ + 1), 469.1
(M+ + Na). Anal. Calcd for C23H27ClN2O5: C, 61.81; H, 6.09;
Cl, 7.93; N, 6.27. Found: C, 62.05; H, 5.93; Cl, 7.77; N, 6.12.
(3S,1′S)-3-Ben zyl-4-(p -m et h oxyb en zyl)-1-(1′m et h oxy-
ca r bon yl)eth yl-2,5-d ioxop ip er a zin e (18). A solution of
compound 17 (0.195 g, 0.44 mmol) in CH3CN (4 mL) was
treated with NaH (21 mg, 0.88 mmol) or Cs2CO3 (0.28 g, 0.88
mmol) and stirred at room temperature for 20 min and 2 h,
respectively. Then, each reaction was acidified to pH 6, the
CH3CN was evaporated and the aqueous solution was ex-
tracted with EtOAc. The organic layer was dried (Na2SO4) and
evaporated, leaving a resulting residue was purified on a silica
gel column, using EtOAc/hexane (1:4), to give 118 mg (66%)
and 120 mg (67%, 84:16 3S,1′S/3R,1′S epimeric mixture),
C
23H26N2O5: C, 67.30; H, 6.38; N, 6.82. Found: C, 67.24; H,
6.16; N, 6.57.
Bzl-R-Me-Azn -L-P h e-OMe (12h and 13h ). Yield: 82%
(from 10h , and H-L-Phe-OMe), 12h :13h ) 50:50. Eluent:
gradient from 50 to 65% of EtOAc in hexane. Isomer (R,S)
12h : HPLC: tR ) 19.12 min (A:B ) 30:70). [R]D ) -18.1 (c )
0.84, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.33-6.98 (m,
10H), 6.13 (d, 1H, J ) 8.0), 4.69 (m, 1H), 4.36 (d, 1H, J ) 15.1),
4.29 (d, 1H, J ) 15.1), 3.71 (s, 3H), 3.09 (dd, 1H, J ) 13.9,
5.4), 2.77 (m, 2H), 2.73 (dd, 1H, J ) 13.9, 7.9), 1.38 (s, 3H).
13C NMR (50 MHz, CDCl3): δ 171.42, 171.14, 166.32, 136.20,
135.80, 128.68, 128.45, 128.40, 128.21, 127.56, 126.75, 59.80,
52.72, 52.03, 49.84, 44.52, 36.89, 19.70. MS (ES, positive
mode): 381.2 (M+ + 1). Anal. Calcd for C22H24N2O4: C, 69.46;
H, 6.36; N, 7.36. Found: C, 69.31; H, 6.15; N, 7.22. Isomer
(S,S) 13h : HPLC: tR ) 20.50 min (A:B ) 30:70). [R]D ) +75.7
(c ) 0.68, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.34-7.03
(m, 10H), 6.26 (d, 1H, J ) 7.8), 4.69 (m, 1H), 4.35 (d, 1H, J )
15.3), 4.02 (d, 1H, J ) 15.3), 3.69 (s, 3H), 3.15 (d, 1H, J )
14.8), 3.01 (dd, 1H, J ) 14.0, 6.2), 2.83 (d, 1H, J ) 14.8), 2.78
(dd, 1H, J ) 14.0, 7.3), 1.35 (s, 3H). 13C NMR (50 MHz,
CDCl3): δ 171.47, 171.44, 166.80, 136.19, 135.82, 129.03,
128.97, 128.70, 128.63, 128.01, 127.30, 60.23, 53.17, 52.39,
50.26, 44.80, 37.37, 19.92. MS (ES, positive mode): 381.2 (M+

Synthesis of 4-Alkyl-4-carboxy-2-azetidinones
J . Org. Chem., Vol. 66, No. 10, 2001 3547
respectively, of the title compound. HPLC: tR ) 12.98 min (A:B
) 35:65). [R]D ) -31.6 (c ) 1.09, CHCl3). H NMR (400 MHz,
(M+ + Na). Anal. Calcd for C23H26N2O5: C, 67.30;H, 6.38; N,
6.82 Found: C, 67.18; H, 6.44; N, 6.65.
1
CDCl3): δ 7.27-6.83 (m, 9H), 5.33 (d, 1H, J ) 14.6), 5.14 (q,
1H, J ) 7.5), 4.17 (m, 1H), 3.94 (d, 1H, J ) 14.6), 3.75 (s, 3H),
3.63 (s, 3H,), 3.42 (d, 1H, J ) 16.7), 3.10 (m, 2H), 2.42 (d, 1H,
J ) 16.7), 1.09 (d, 3H, J ) 7.5). 13C NMR (75 MHz, CDCl3): δ
170.73, 165.64, 164.19, 159.34, 134.64, 129.99, 129.77, 129.65,
128.69, 127.78, 114.36, 59.72, 55.14, 52.35, 50.37, 46.36, 45.48,
36.68, 13.33. MS (ES, positive mode): 411.1 (M+ + 1), 433.2
Ack n ow led gm en t. We thank the Comisio´n Inter-
ministerial de Ciencia y Tecnolog´ıa (SAF 97 0030 and
SAF 2000-0147) for financial support. G.G.N. is a
predoctoral fellow from the Ministerio de Educacio´n y
Cultura, Spain.
J O015559B