Construction of quaternary stereogenic centers via [2 + 2] cycloaddition reactions. Synthesis of homochiral 4,4-disubstituted 2-azetidinones and imine substituent effects on β-lactam formation

Article abstract of DOI:10.1021/jo962017z

A study on the asymmetric construction of quaternary stereogenic centers via [2 + 2] cycloaddition reaction of ketenes with ketimines is described. Reaction of achiral ketenes and chiral α-alkoxy ketone-derived imines resulted in formation of new β-lactams as single diastereomers. The cycloaddition was extended to pyruvate imines, aralkyl ketone-derived imines, and dialkyl ketimines. In these cases the asymmetric induction was satisfactorily achieved using β-silylalkanoyl ketenes and the Evans-Sjogren ketene. C,C-Bis (trimethylsilyl)methylamine ketimines derived from enolizable dialkyl ketones cleanly led to the corresponding C(4) disubstituted β-lactams without deprotonation. Therefore, a general methodology for a convergent asymmetric synthesis of β-lactams in which C(4) exists as a quaternary carbon is provided.

Full text of DOI:10.1021/jo962017z

2070
J . Org. Chem. 1997, 62, 2070-2079
Con str u ction of Qu a ter n a r y Ster eogen ic Cen ter s via [2 + 2]
Cycloa d d ition Rea ction s. Syn th esis of Hom och ir a l
4,4-Disu bstitu ted 2-Azetid in on es a n d Im in e Su bstitu en t Effects on
â-La cta m F or m a tion
Claudio Palomo,*,1a J esus M. Aizpurua,1a J esus M. Garc´ıa,1a,1b Regina Galarza,1a
Marta Legido,1a Raquel Urchegui,1a Pascual Roma´n,1c Antonio Luque,1c
J uan Server-Carrio´,1d and Anthony Linden1e
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad del Pais Vasco, Apdo 1072,
20080 San Sebastia´n, Spain, Departamento de Qu´ımica Inorga´nica, Universidad del Pais Vasco,
Apdo 644, 48080 Bilbao, Spain, and Organisch-Chemisches Institut der Universita¨t Zu¨rich,
Winterthurerstrasse 190, CH-8057 Zu¨rich, Switzerland
Received October 29, 1996X
A study on the asymmetric construction of quaternary stereogenic centers via [2 + 2] cycloaddition
reaction of ketenes with ketimines is described. Reaction of achiral ketenes and chiral R-alkoxy
ketone-derived imines resulted in formation of new â-lactams as single diastereomers. The
cycloaddition was extended to pyruvate imines, aralkyl ketone-derived imines, and dialkyl ketimines.
In these cases the asymmetric induction was satisfactorily achieved using â-silylalkanoyl ketenes
and the Evans-Sjo¨gren ketene. C,C-Bis (trimethylsilyl)methylamine ketimines derived from
enolizable dialkyl ketones cleanly led to the corresponding C(4) disubstituted â-lactams without
deprotonation. Therefore, a general methodology for a convergent asymmetric synthesis of â-lactams
in which C(4) exists as a quaternary carbon is provided.
In tr od u ction
which generate these small rings in a single step have
been the subject of very few investigations.5 Virtually
all of these studies are based on photochemical reactions
of alkenes, although the thermal cycloaddition of dichlo-
roketene with chiral enol ethers has also been docu-
mented.6
Synthesis of molecules with a quaternary carbon center
as building blocks for natural products and biologically
active compounds is an active area of investigation and
often presents a number of important synthetic chal-
lenges.2 A variety of methods have been developed to
satisfactorily accomplish this goal.3 These methods can
be categorized into two main groups: those involving
enantioselective synthesis and those involving diaste-
reoselective creation of quaternary centers. The latter
include the usual carbon-carbon bond-forming processes
such as the alkylation of chiral enamines and enolates,
the aldol reaction, the asymmetric Michael addition, and
the Diels-Alder cycloaddition.4 Successful implementa-
tion of these procedures to heterocyclic synthesis has
provided expedient approaches to five- and six-membered
rings, often embodied in a wide variety of natural
products. However, methodologies for construction of
four-membered rings with quaternary stereogenic centers
are still scarce. In this context, [2 + 2] cycloadditions
Among the many targets that might be obtained by [2
+ 2] cycloadditions, â-lactams with quaternary stereo-
genic centers at the C(4) position are of particular interest
for several reasons. The â-lactam ring is the key
structural element of the most widely employed class of
antimicrobial agents, the â-lactam antibiotics.7 Conse-
quently, understanding the reactivity of 4,4-disubstituted
â-lactams would provide new opportunities for the study
of structure-activity relationships and further insight
into the design of new antibiotics and/or enzyme inhibi-
tors.8 In fact, the discovery by the Squibb group9 that
tigemonam, Figure 1, possesses superior activity than
other oral â-lactam antibiotics, specially when the patho-
gen was a â-lactamase producer, firmly establishes the
necessity to address the problem of the stereocontrolled
synthesis of 4,4-disubstituted â-lactams. In addition to
X Abstract published in Advance ACS Abstracts, March 1, 1997.
(1) (a) Universidad del Pa´ıs Vasco, San Sebastian. (b) Permanent
address: Departamento de Quimica, Universidad Publica de Navarra,
31006-Pamplona, Navarra, Spain. (c) Universidad del Pa´ıs Vasco,
Bilbao. X-ray analysis of compound 22b. (d) Departamento de Qu´ımica
Inorganica, Facultad de Farmacia, Universidad de Valencia, 46100-
Valencia, Spain. (e) Universita¨t Zu¨rich. X-ray analysis of compound
37d .
(5) Butenolides: (a) Miller, M. Hegedus, L. S. J . Org. Chem. 1993,
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S0022-3263(96)02017-8 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Homochiral 4,4-Disubstituted 2-Azetidinones
J . Org. Chem., Vol. 62, No. 7, 1997 2071
F igu r e 1.
these general aspects, work in this laboratory10 and
others11 suggests that â-lactams with quaternary stereo-
genic centers at the C(4) position would be powerful,
small building blocks for natural product synthesis,
Figure 2, providing access to a wide variety of non-â-
lactam products.
Thus, we have studied diastereoselective synthesis of
â-lactams with quaternary stereogenic centers at C(4)
using [2 + 2] cycloaddition reactions. Results of this
study are presented below.
Resu lts a n d Discu ssion
F igu r e 2. Potential uses of a â-lactam framework with a
Prior to the present study, no efficient strategies either
for the creation of quaternary centers at the C(4) position
of the â-lactam ring or for controlling the stereochemistry
at the newly created stereogenic centers have been
quaternary stereogenic center at the C(4) position.
described in the literature.12 In a pioneering approach,
Slusarchyk and Godfrey13 applied the well established
hydroxamate methodology13c to the formation of C(4)
disubstituted â-lactams, but the method was overshad-
owed by rearrangement processes. Ternansky and Mor-
in14 reiterate the fact that, in general, most of the
methods reported thus far for the synthesis of the
â-lactam ring do not satisfactorily address this synthetic
challenge. Consequently, we undertook a study on this
subject and found that the cycloaddition of ketenes,
generated from acid chlorides and triethylamine, with
ketimines fulfills the above criteria and provides a
general route to optically active â-lactams in which C(4)
exists as a quaternary carbon.15 Since this work repre-
sents the first systematic study on this topic, the scope
and limitations of the cycloaddition reaction were ex-
plored by using a number of structurally different
ketimines, i.e. R-alkoxy ketone-derived imines, pyruvate
imines, aralkyl ketone-derived imines, and dialkyl
ketimines. During the course of our investigations, we
found that these ketimines showed different chemical and
stereochemical behavior. Therefore, each class of sub-
strate will be discussed separately.
(10) For representative examples, see: (a) Palomo, C.; Aizpurua, J .
M. Trends Org. Chem. 1993, 4, 637. R-Amino acid N-carboxy anhy-
drides: (b) Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Carreaux, F.;
Cuevas, C.; Maneiro, E.; Ontoria, J . M. J . Org. Chem. 1994, 59, 3123.
(c) Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Maneiro, E.; Odriozola, B.
J . Chem. Soc., Chem. Commun. 1994, 1505. R-Hydroxy â-amino acid-
derived peptides: (d) Palomo, C.; Aizpurua, J . M.; Cabre´, F.; Garc´ıa,
J . M.; Odriozola, J . M. Tetrahedron Lett. 1994, 35, 2721. (e) Palomo,
C.; Aizpurua, J . M.; Cuevas, C. J . Chem. Soc., Chem. Commun. 1994,
1957. 1,3-Polyols and 2-amino-1,3-polyols: (f) Palomo, C.; Aizpurua,
J . M.; Urchegui, R.; Garc´ıa, J . M. J . Org. Chem. 1993, 58, 1646.
â-Amino ketones: (g) Palomo, C.; Aizpurua, J . M.; Garc´ıa, J . M.;
Iturburu, M.; Odriozola, J . M. J . Org. Chem. 1994, 59, 5184. R-Amino
acid peptide fragments of lysobactin: (h) Palomo, C.; Aizpurua, J . M.;
Ganboa, I.; Odriozola, B.; Maneiro, E.; Miranda, J . I.; Urchegui, R. J .
Chem. Soc., Chem. Commun. 1996, 161. R-Branched â-alkylserine pep-
tides: (i) Palomo, C.; Aizpurua, J . M.; Urchegui, R.; Garc´ıa, J . M. J .
Chem. Soc., Chem. Commun. 1995, 2327. â-Substituted aspartic
acids: (j) Palomo, C.; Cabre´, F.; Ontoria, J . M. Tetrahedron Lett. 1992,
33, 4819. (k) Palomo, C.; Aizpurua, J . M.; Ontoria, J . M.; Iturburu, M.
Tetrahedron Lett. 1992, 33, 4823. (l) Palomo, C.; Aizpurua, J . M.;
Ganboa, I. In Enantioselective Synthesis of â-Amino Acids; J uaristi,
E., Ed.; VCH: New York, 1997, in press.
(11) For reviews of non-â-lactam products from azetidinone frame-
works, see: (a) Manhas, M. S.; Wagle, D. R.; Chiang, J .; Bose, A. K.
Heterocycles 1988, 27, 1755. (b) Hesse, M. In Ring Enlargement in
Organic Synthesis; VCH: Weinheim, 1991; p 97. Amino acids and
peptides: (c) Ojima, I. In The Organic Chemistry of â-Lactams; Georg,
G. I., Ed., VCH: New York, 1992; p 197. (d) Ojima, I. Acc. Chem. Res.
1995, 28, 383. (e) Hegedus, L. S. Acc. Chem. Res. 1995, 28, 299.
Aspartic acids: (f) Hanessian, S.; Sumi, K.; Vanasse, B. Synlett 1992,
23. R,â-Diamino acids: (g) Ojima, I.; Pei, Y. Tetrahedron Lett. 1990,
31, 977. Polyhydroxyamino acids: (h) Banick, B. K.; Manhas, M. S.;
Bose, A. K. J . Org. Chem. 1993, 58, 307. γ-Keto R-amino acids: (i)
Baldwin, J . E.; Adlington, R. M.; Godfrey, C. R. A.; Gollins, D. W.;
Smith, M. L.; Russel, A. T. Synlett 1993, 51. (j) Baldwin, J . E.;
Adlington, R. M.; Rusell, A. T.; Smith, M. L. Tetrahedron Lett. 1995,
51, 4733. Prolines: (k) Baldwin, J . E.; Adlington, R. M.; Godfrey, C.
R. A.; Gollins, D. W.; Vaughan, J . G. J . Chem. Soc., Chem. Commun.
1993, 1434. (l) Baldwin, J . E.; Rudolph, M. Tetrahedron Lett. 1994,
35, 6163. Aminosugars: (m) Ha, D.-C.; Hart, D. J . Tetrahedron Lett.
1987, 28, 4489. (n) Shiozaki, M.; Ishida, N.; Sato, S. Bull. Chem. Soc.
J pn. 1989, 62, 3950. (o) Galluci, J . C.; Ha, D.-C.; Hart, D. J .
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R. P. J . Org. Chem. 1987, 52, 5041. (q) Araki, K.; O’Toole, J . C.; Welch,
J . T. Bioorg. Med. Chem. Lett. 1993, 3, 2457. (r) Bose, A. K.; Mathur,
C.; Wagle, D. R.; Naqvi, R.; Manhas, M. S. Heterocycles 1994, 39, 491.
Pyrrolizidines: (s) Cavanga, F.; Linkies, H.; Pietsch, H.; Reuschling,
D. Angew. Chem., Int. Ed. Engl. 1980, 129. Pyrrolidines: (t) Bose, A.
K.; Krishnan, L.; Wagle, D. R.; Manhas, M. S. Tetrahedron Lett. 1986,
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L.; Manhas, M. S.; Bose, A. K. J . Chem. Soc., Chem. Commun. 1989,
8915.
Cycloa d d ition s of r-Alk oxy Keton e-Der ived Im i-
n es. Recent reports from this laboratory and others have
(12) For methodology to create quaternary stereogenic centers at
the C(3) position, see: (a) ref 11c,d. (b) Thompson, D. K.; Suzuki, N.;
Hegedus, L. S.; Satoh, Y. J . Org. Chem. 1992, 57, 1461. (c) Colson, P.
J .; Hegedus, L. S. J . Org. Chem. 1993, 58, 5918.
(13) (a) Slusarchyk, W. A.; Dejneka, T.; Gougoutas, J .; Koster, W.
H.; Kronenthal, D. R.; Malley, M.; Perri, M. G.; Routh, F. L.; Sundeen,
J . E.; Weaver, E. R.; Zahler, R.; Godfrey, J . D., J r.; Mueller, R. H.;
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J r.; Mueller, R. H.; VonLangen, D. J . Tetrahedron Lett. 1986, 27, 2793.
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(14) Ternansky, R. J .; Morin, J . M., J r. In The Organic Chemistry
of â-Lactams; Georg, G. I., Ed., VCH: New York, 1992; p 257.
(15) For reviews on cycloaddition of ketenes with imines, see: (a)
Backes, J . In Houben-Weil Methoden der Organischen Chemie; Mueller,
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(e) Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of
â-Lactams; Georg, G. I., Ed.; VCH: New York, 1992; p 295.

2072 J . Org. Chem., Vol. 62, No. 7, 1997
Palomo et al.
Sch em e 2
F igu r e 3.
Sch em e 1
and monoalkylketenes failed to react with 3a . In order
to establish the scope of this alkoxyketene-ketimine
cycloaddition, we subjected ketimines 3b, 3c, and 3d to
treatment with (benzyloxy)acetyl chloride and triethyl-
amine under the above reaction conditions. In every
case, a single â-lactam product was detected by 1H-NMR
analysis of the corresponding crude reaction mixture, and
in each case a strong NOE (≈13%) was observed between
the alkyl group protons at the C(4) position and the C(3)-
hydrogen, indicating that these two units were in a syn
relationship. This is particularly significant when a new
â-lactam product of previously unassigned absolute ster-
eochemistry is prepared.
documented that cycloaddition reactions of ketenes with
both R-alkoxy aldehyde-derived imines16 and N-Boc
R-amino aldehyde-derived imines17 give complete induc-
tion of asymmetry from the starting imines to the newly
created stereogenic centers. In contrast, the potential
in asymmetric synthesis of the cycloaddition of ketenes
with R-alkoxy ketone-derived imines has yet to be
demonstrated. Therefore, we investigated this reaction
through application of the recently advanced origins of
the asymmetric induction.17a,b
The starting ketimines employed in this study (Figure
3) were prepared by condensation of the corresponding
R-alkoxy ketones with the respective amines promoted
by TiCl4 following Weingarten’s procedure.18 Otherwise,
a loss of optical purity was observed, vide infra, in the
formation of the corresponding cycloadducts.
To assay the diastereoselection for this reaction, the
ketimines 1a , 1b, 2a , and 3a were treated with (benzyl-
oxy)ketene, generated from (benzyloxy)acetyl chloride
and triethylamine at low temperature (Scheme 1). The
experiments revealed that treatment of both 1a and 1b
with (benzyloxy)ketene in methylene chloride at -78 °C
to room temperature overnight resulted in the formation
of a complex mixture in which we did not detect the
expected â-lactam products. Under identical conditions
ketimine 2a led to â-lactam formation, although a
mixture of diastereomeric â-lactams 5 and 6 was obtained
in a ratio 70:30, respectively. Finally, we observed that
3a efficiently produced 7a in 85% yield and, most notably,
with high diastereoselectivity. However, some limita-
tions arose when the reaction was applied to different
ketenes. For instance, haloketenes, (phenylthio)ketene,
To establish whether racemization occurred during the
process of â-lactam formation, each compound 7 was
subjected to hydrogenolysis, and the resulting 3-hydroxy
â-lactams 8a -d were acylated with (+)-MTPA acid
chloride19 and triethylamine in the presence of DMAP
as catalyst (Scheme 2). HPLC analysis of the resulting
Mosher esters 9 showed homogeneous material under
conditions that cleanly resolved the corresponding esters
derived from racemic material. In addition, all of these
1
derivatives showed a single set of signals in the H, 13C,
and 19F NMR spectra, thus confirming the absence of
racemization during ketimine formation and cycloaddi-
tion reaction. The temperature effect on the enantio-
meric purity of benzyl ketimines 3 and, hence, â-lactams
7 was evidenced preparing the N-benzyl imine 3a from
benzylamine and the corresponding ketone at room
temperature without TiCl4. (Benzyloxy)ketene cycload-
dition under the above conditions afforded a 70:30
mixture of 7a and its enantiomer, respectively, as
determined by the Mosher test. Finally, to assess the
stereochemical assignment, compound 8b was submitted
to a single-crystal X-ray analysis.20 Results of the
cycloaddition reaction with different N-benzyl imines are
listed in Table 1 (compounds 7a -d ) and show the
effectiveness of this reaction to create quaternary centers,
with predictable stereochemistry.
On the basis of results presented in Table 1, the imine
4, upon treatment with (benzyloxy)ketene should gener-
ate the â-lactam 10 with absolute C(4) stereochemistry
opposite to that observed for cycloadducts 7. Indeed, as
shown in Scheme 3, this was the case, and the absolute
configuration of 10 was established by chemical correla-
tion with 7a . This correlation was carried out by conver-
sion of 10 into the 4-carboxy â-lactam 12 by simple
removal of the acetonide group in 10 followed by oxidative
cleavage of the resulting glycol 11. On the other hand,
(16) (a) Hubschwerlen, C.; Schmid, G. Helv. Chim. Acta 1983, 66,
2206. (b) Wagle, D. R.; Garai, G.; 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. (c) Evans, D. A.; Williams, J . M.
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Staszak, M. A.; Weigel, L. D. Tetrahedron Lett. 1992, 33, 857.
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Roman, P.; Luque, A.; Martinez-Ripoll, M. J . Am. Chem. Soc. 1992,
114, 9360. (b) Cossio, F. P.; Lecea, B.; Cuevas, C.; Mielgo, A.; Palomo,
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S.; Bhawal, B. M. Synlett 1992, 749.
(19) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(18) (a) Weingarten, H.; Chupp, S. P.; White, W. A. J . Org. Chem.
1967, 32, 3246. (b) Sotomayor, N.; Vicente, T.; Dominguez, E.; Lete,
E.; Villa, M. J . Tetrahedron 1994, 50, 2207. (c) Moss, N.; Gauthier, J .;
Ferland, J .-M. Synlett. 1994, 142.
(20) For X-ray data and synthetic application in R-amino acid
chemistry of the â-lactams prepared, see ref 10i and Palomo, C.;
Aizpurua, J . M.; Ganboa, I.; Odriozola, B.; Urchegui, R.; Go¨rls, H. J .
Chem. Soc., Chem. Commun. 1996, 1269.

Synthesis of Homochiral 4,4-Disubstituted 2-Azetidinones
J . Org. Chem., Vol. 62, No. 7, 1997 2073
Ta ble 1. C3-Alk oxy- a n d C3-a lk yl- C4-d isu bstitu ted â-la cta m s P r ep a r ed by Asym m etr ic Keten e-im in e [2 + 2]
Cycloa d d ition
Sch em e 3
â-lactam 13 in 88% overall yield. Subsequent ozonolysis
of the corresponding trimethylsilyl enol ether led to the
â-lactam 14 which was found to be the enantiomer of 12.
Enantiomerically pure 4-carboxy â-lactams are of diverse
interest. For instance, ring opening is expected to give
R-branched â-alkoxy aspartic acid derivatives which
would be valuable elements for the design of conforma-
tionally restricted peptides.21
Another very useful reaction for â-lactam ring con-
struction is the addition of metallo ester enolates to
imines, a reaction that has been widely documented in
the literature.22 However, the lower reactivity of keti-
mines, when compared with that of aldimines, and their
competitive R-deprotonation, makes the ester enolate-
imine condensation impracticable for the synthesis of
â-lactams disubstituted at the C(4) position. Indeed, the
significance of the cycloaddition as the key reaction for
diastereoselective construction of quaternary centers was
Sch em e 4
(21) For example, â-alkoxy aspartic acids, occurring in macrocyclic
antibiotics, have been incorporated into peptides by the sodium azide-
promoted reaction of N-Boc-3-alkoxy-4-alkoxycarbonyl â-lactams with
R-amino acid esters. More detailed information is provided in refs 10e
and 10h.
(22) Reviews: (a) Hart, D. J .; Ha, D.-C. Chem. Rev. 1989, 89, 1447.
(b) Brown, M. J . Heterocycles 1989, 29, 2225. (c) Georg, G. I. In Studies
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dam, 1989; Vol. 4, p 431. (d) Fujisawa, T.; Shimizu, M. Rev. Heteroatom
Chem. 1996, 15, 203. (e) Cainelli, G.; Panuncio, M.; Andreoli, P.;
Martelli, G.; Spunta, G.; Giacomini, D.; Bandini, E. Pure Appl. Chem.
1990, 62, 605.
as shown in Scheme 4, 7a was desilylated and the
resulting hydroxy compound oxidized to the 4-acetyl

2074 J . Org. Chem., Vol. 62, No. 7, 1997
Palomo et al.
Sch em e 7
F igu r e 4.
Sch em e 5
Ta ble 2. C3-Am id o- C4-d isu bstitu ted â-la cta m s P r ep a r ed
by Asym m etr ic Keten e-im in e [2 + 2] Cycloa d d ition
Sch em e 6
com-
yielda
(%)
deb
pound R1
R2
R3
(%) mpc (°C)
26a
26b
26c
32a
32b
32c
Me CO2Me
Me CO2Me
Me CO2Me
Me Ph
C6H4OMe-p 60 (36)
CH(SiMe3)2 39 (33)
20d 165-166
10d 136-138
20d oil
Bn
Bn
Bn
68 (41)
65 (65) >98 145-146
Me C6H4OMe-p
65 (65) >98 143-144
emphasized by the failure of the titanium or lithium
enolates derived from 2-pyridyl thioester 1523 to give the
expected cycloadducts with the ketimine 3a using the
same conditions to transform the parent aldehyde-
derived imine 16 into 17 (Scheme 5).
Me (E)-CHdCHPh Bn
77 (67)
80 168-170
35a e Me Me
CH(SiMe3)2
CH(SiMe3)2
CH(SiMe3)2
CH(SiMe3)2
CH(SiMe3)2
70 >98 101-103
69 >98 101-102
70 >98 195-197
35be Et
Et
35ce nPr nPr
35d e Me Et
80f
60f
70 124-126
44 120-122
40 142-144
66 oil
35ee Me CH2CH2Ph
35f
35g
H
H
Me
CH2CH2Ph
CH(SiMe3)2 75 (49)
CH(SiMe3)2 78 (60)
Cycloa d d ition s of P yr u va te Im in es. Interest in
4-alkoxycarbonyl â-lactams as antibiotics and as masked
forms of aspartic acid derivatives led our exploration to
pyruvate imines 18 (Figure 4). Since these starting
materials were achiral, asymmetric induction required
the use of chiral ketenes. The first system examined was
based on previous studies using unactivated ketenes and
glyoxylate imines for the production of 3-alkyl â-lac-
tams.24 We elected to use â-silylalkylketenes (Scheme
6), generated from optically active â-silylalkanoyl chlo-
rides and triethylamine, for two reasons. First, the silyl
group can be removed from the reaction product after the
stereochemical control has been effected; second, it can
be converted into a hydroxyl group with retention of
configuration.25 As a consequence, the resulting cycload-
ducts could be transformed into either â-alkyl R,R-
disubstituted aspartates10k or branched aminosugars11m,n
and also might be employed as precursors of structurally
modified new carbapenems.26 As shown in Scheme 6,
reaction of the â-(dimethylphenylsilyl)butanoyl chloride
(19)27 with the pyruvate imine 18a in the presence of
triethylamine led to the formation of the â-lactam product
a
Yield of isolated reaction mixture. Isolated major product yield
in parentheses. Determined by 300 MHz 1H-NMR spectroscopy.
b
de values refer to both cis diastereomers. c Solid compounds were
crystallized from hexane, and oily products were purified by
d
preparative HPLC. de value referred to C3 (R) and (S) cis stereo-
isomers. e For reaction conditions, see Scheme 10. f Reaction car-
ried out using a two-fold excess of acid chloride.
21 together with its diastereomer 23 in a ratio of 75:25.
A somewhat better result was obtained when the reaction
was performed with the acid chloride 20 to give â-lactams
22/24 in a ratio of 90:10, respectively. Next, for reasons
that will be outlined later, we investigated the pyruvate
imine 18b for such a cycloaddition. Although chemical
yields and stereoselectivities were analogous to that from
18a (see Table 1), the N-bis(trimethylsilyl)methyl moiety
could be removed cleanly by the action of cerium(IV)
ammonium nitrate to give the corresponding N-H-azeti-
din-2-ones in theoretical yields and without the necessity
of further purifications, vide infra. The sense of asym-
metric induction for these reactions was established on
the basis of a single crystal X-ray analysis of the
cycloadduct 22b (see Experimental Section) and by the
assumption of a uniform reaction mechanism.
At this stage, we sought out alternative ketenes with
the aim to improve the stereochemical outcome of the
above cycloadditions. Literature precedent covering this
topic suggested that the Evans-Sjo¨gren ketene,28 derived
from 25, Scheme 7, should be the most suitable candidate
to achieve high levels of reaction diastereoselection.
However, as shown in Table 2, while the above chiral
alkylketenes gave reasonably good stereochemical out-
come for cycloadditions, the pyruvate imines 18 on
treatment with 25 and triethylamine failed to produce
(23) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Ponzini,
F. J . Org. Chem. 1993, 58, 4746.
(24) Palomo, C.; Aizpurua, J . M.; Urchegui, R.; Iturburu, M. J . Org.
Chem. 1992, 57, 1571.
(25) (a) Fleming, I. Pure Appl. Chem. 1988, 60, 71. (b) Hwu, J . R.;
Wang, N. Chem. Rev. 1989, 89, 1599. (c) Ager, D. J .; East, M. B.
Tetrahedron 1992, 48, 2803.
(26) Owing to the easy conversion of the 4-alkoxycarbonyl group into
different functional groups and/or the possibility to replace it directly
by alkyl chains via decarboxylative radical conjugate addition to
Michael acceptors, renders these azetidinones attractive potential
building-blocks in â-lactam chemistry. See for example ref. 22 and (a)
Sumi, K.; DiFabio, R.; Hanessian, S. Tetrahedron Lett. 1992, 33, 749.
(b) Veiberg, G. A.; Lukevics, E. Heterocycles 1994, 38, 2309. (c) Kant,
J .; Walker, D. G. In “The Organic Chemistry of â-Lactams”, Georg, G.
I. Ed. VCH: New York, 1992, p 121. (d) Kametani, T. Heterocycles
1982, 17, 463.
(27) For the preparation of homochiral â-silylalkanoyl chlorides,
see: Palomo, C.; Aizpurua, J . M.; Iturburu, M.; Urchegui, R. J . Org.
Chem. 1994, 59, 240, and references therein.
(28) (a) Evans, D. A.; Sjo¨gren, E. B. Tetrahedron Lett. 1985, 26, 3783.
(b) Evans, D. A.; Sjo¨gren, E. B. Ibid. 1985, 26, 3788.

Synthesis of Homochiral 4,4-Disubstituted 2-Azetidinones
J . Org. Chem., Vol. 62, No. 7, 1997 2075
Sch em e 8
Sch em e 9
good diastereoselectivity. For example, reaction of the
ketene derived from 25 and the pyruvate imine 18a
furnished a mixture of 26a and 27a in a diastereomeric
ratio of 60:40, respectively. In a similar way, the pyru-
vate imines 18b and 18c led to the corresponding
â-lactams 26b,c and 27b,c without diastereoselection. In
each â-lactam product, the NOE observed ≈10% between
the methyl group at the C(4) position and the C(3)-
hydrogen suggested a relative cis-stereochemistry for the
adducts.
To confirm the proposed stereochemistry, the major
isomer 26c was transformed, Scheme 8, into the hy-
droxymethyl derivative 28, and this into the 4,4-dimeth-
ylazetidinone 29, which was also obtained by another
independent route, vide infra.
Cycloa d d ition s of Ar a lk yl Keton e-Der ived Im i-
n es. Next, we evaluated the behavior of other achiral
ketimines in such a cycloaddition process from both
chemical and stereochemical standpoints. Prior to the
present study, Hegedus and co-workers29 reported the
cycloaddition reaction of asymmetric ketenes, generated
by photolysis of chromium aminocarbene complexes, with
acetone benzyl imine (eq 1). In this process, however, a
modest level of asymmetric induction, 70% de, which
contrasts with that obtained using aldehyde-derived
imines, was attained. Therefore, we were intrigued by
the question of whether asymmetric induction could be
effected employing the chiral ketene derived from 25.
genic center of the oxazolidinone moiety, while the
absolute configuration of the C(4) position is dictated by
the cis/ trans specificity of the â-lactam-forming process.30
To test this hypothesis, the â-lactam product 32c was
transformed into the hydroxymethyl derivative 28 which
was identical to that obtained by reduction of the meth-
oxycarbonyl group in 26c, vide supra.
With these results in hand, a direct comparison
between the chemistry in eq 1 and reactions in Scheme
9 can be made. In particular, the high level of diaste-
reoselectivity seems to be the most significant feature of
these reactions although chemical yields were also good.
However, attempts to extend this approach to ketimines
derived from more easily enolizable ketones, i.e. dialkyl
ketone-derived imines, resulted in the formation of
enamides, along with substantial amounts of hydrolysis
product. Consequently, at this stage we focused on this
problem which also appears to be general for cycloaddi-
tions involving enolizable aldehyde-derived imines.31
Cycloa d d ition s of Dia lk yl Keton e-Der ived Im i-
n es. Stimulated by the clinical development of the
monocyclic â-lactam tigemonam,9b we investigated the
problem of preparing 4,4-dialkyl â-lactams via this
ketene-ketimine cycloaddition reaction. We reasoned
that this convergent approach would be complementary
to the hydroxamate methodology, overcoming drawbacks
like dehydration, rearrangement processes,13 or the need
for a highly diastereoselective access to the starting chiral
â-hydroxy acids with quaternary centers at the â-position
which are not readily available or not easy to prepare.32
Recent semiempirical studies indicate that the cycload-
dition of ketenes with imines to form â-lactams occurs
through a zwitterionic intermediate.30 It follows that any
structural change that would serve to stabilize this
intermediate and/or to circumvent competitive deproto-
nations should assist the â-lactam-forming process. A
potential solution to the aforementioned problem may be
inferred from the known ability of silicon to influence the
reactivity at electron-deficient â- and γ-centers.33 In the
course of our studies on carbon-carbon bond-forming
reactions, we have developed the C,C-bis(trimethylsilyl)-
(1)
The reaction of oxazolidinylacetic acid chloride 25 and
triethylamine, Scheme 9, with ketimines 30a -c and
31a -c was examined. In each case the reaction was
conducted at low temperature by adding 25 to a solution
of the corresponding ketimine and triethylamine. Under
these conditions the corresponding â-lactam products
32a -c, and 33a -c were obtained in yields ranging from
60% to 70%, and in each case as single diastereomers.
This result implies that, in principle, the stereochemical
course of the reaction corresponds to that observed for
aldimines, and, therefore, the general pattern seems to
be unaffected by the presence of alkyl substituents on
the ketimine component. The absolute stereochemistry
at the C(3) position of the resulting cycloadducts is
completely governed by the configuration of the stereo-
(30) (a) Cossio, F. P.; Ugalde, J . M.; Lopez, X.; Lecea, B.; Palomo,
C. J . Am. Chem. Soc. 1993, 115, 995. (b) Sordo, J . A.; Gonzalez, J .;
Sordo, T. L. J . Am. Chem. Soc. 1992, 114, 6249. (c) Arrieta, A.; Lecea,
B.; Ugalde, J . M. J . Am. Chem. Soc. 1994, 116, 2085.
(31) Palomo, C.; Aizpurua, J . M.; Legido, M.; Galarza, R.; Deya, P.
M.; Dunogues, J .; Picard, J . P.; Ricci, A.; Seconi, G. Angew. Chem.,
Int. Ed. Engl. 1996, 11, 1239.
(32) After completion of this work,
a paper dealing with the
synthesis of 4,4-disubstituted â-lactams via hydroxamate methodology
has been appeared. See: Ageno, G.; Banfi, L.; Cascio, G.; Guanti, G.;
Manghisi, E.; Riva, R.; Rocca, V. Tetrahedron 1995, 51, 8121.
(33) Review: Lambert, J . B. Tetrahedron 1990, 46, 2677.
(29) Hegedus, L. S.; Imiwinkelried, R.; Alarid-Sargent, M.; Dvorak,
D.; Satoh, Y. J . Am. Chem. Soc. 1990, 112, 1109.

2076 J . Org. Chem., Vol. 62, No. 7, 1997
Palomo et al.
Sch em e 10
Sch em e 11
methylamine34 as an R-aminomethyl carbanion equiva-
lent and applied it to the synthesis of azadienes,35
enamides and 1,2-dihydroisoquinolines,36 pyrrolidines,37
and bicyclic â-lactam compounds.38 Therefore, to test the
above hypothesis, the behavior of representative ketimines
derived from this silyl-based methylamine reagent was
examined.39
Sch em e 12
The reaction of imine 34a , Scheme 10, with the ketene
derived from 25 was first carried out at low temperature
as in the previous cases. The expected â-lactam 35a was
formed, albeit in very poor yield. In contrast, heating a
mixture of 34a , 25, and triethylamine in chloroform, free
of ethanol, at reflux, produced exclusively 35a in 70%
yield. In a similar way, ketimines 34b and 34c produced
the desired cycloadducts 35b and 35c in yields of 69%
and 70%, respectively. When the reaction was examined
from the unsymmetrical ketimines 34d and 34e, two
diastereomeric pairs of â-lactams 35d /36d (65% yield)
and 35e/36e (60% yield) were formed in 70:30 and 62:38
ratios, respectively. In an effort to improve this chemical
yield, we repeated the cycloaddition of ketimine 34d
using a two-fold excess of acid chloride 25. Remarkably,
not only the yield was increased to 80%, but also the
reaction diastereoselectivity improved to a 85:15 ratio.
Under these conditions, the major isomers 35d and 35e
were separated in 45% and 62% yield by silica gel column
chromatography.
subjected to treatment with CAN in methanol as solvent
within about 2 h at room temperature, the N-formyl
derivatives 37a and 37d were produced in >95% yields.
In addition, a single crystal X-ray analysis of 37d (see
Experimental Section) confirmed the initially assigned
relative stereochemistry for 35d . Interestingly, the same
reaction carried out under reflux conditions led to the
N-unsubstituted â-lactams 38a and 38d in a single step,
and in yields of 92% and 90%, respectively.
Alternatively, removal of the oxazolidinone moiety in
35a , Scheme 12, followed by treatment of the resulting
intermediate 3-amino â-lactam with benzyl chloroformate
and DMAP, gave 39 in 65% over the two steps.42
Subsequent exposure of 39 to CAN in acetonitrile-water
and further N-deformylation43 in a slightly basic medium
afforded 40 in 41% overall yield (not improved). Finally,
it should be mentioned that besides the utility of these
â-lactams for the development of â-lactam antibiotics,
they have also found application in the â-amino acid
chemistry.44
Since removal of the N-[bis(trimethylsilyl)methyl] moi-
ety is an indispensable condition for these â-lactams to
find application in â-lactam chemistry, at this stage, we
addressed this issue and, after screening our previously
reported method,40 we found that cerium ammonium
nitrate (CAN) was very effective in promoting the C-Si
bond cleavage.41 Thus, when both 35a and 35d were
(34) The C,C-bis(trimethylsilyl)methylamine can be prepared in
gram quantities by reductive silylation (Li, ClSiMe3, HMPA-THF) of
either cyanotrimethylsilane or N,N-dimethylcyanamide. For details,
see: (a) Picard, J . P.; Grelier, S.; Constantieux, T.; Dunogues, J .;
Aizpurua, J . M.; Palomo, C.; Pe´traud, M.; Barbe, B.; Lunazzi, L.; Leger,
J . M. Organometallics 1993, 12, 1378. (b) Grelier, S.; Constantieux,
T.; Deffieux, D.; Bordeau, M.; Dunogues, J .; Picard, J . P.; Palomo, C.;
Aizpurua, J . M. Organometallics 1994, 13, 3711.
(40) The bis(trimethylsilyl)methyl moiety was first removed using
the following three-step sequence according to the procedure given in
ref 35.
(35) Lasarte, J .; Palomo, C.; Picard, J . P.; Dunogues, J .; Aizpurua,
J . M. J . Chem. Soc., Chem. Commun. 1989, 72.
(36) Palomo, C.; Aizpurua, J . M.; Legido, M.; Picard, J . P.; Dunogues,
J .; Constantieux, T. Tetrahedron Lett. 1992, 33, 3903.
(37) Palomo, C.; Aizpurua, J . M.; Garcı´a, J . M.; Legido, M. J . Chem.
Soc., Chem. Commun. 1991, 524.
(38) (a) Palomo, C.; Aizpurua, J . M.; Garc´ıa, J . M.;Ganboa, I.; Cossio,
F. P.; Lecea, B.; Lopez, C. J . Org. Chem. 1980, 55, 2498. (b) Palomo,
C.; Aizpurua, J . M.; Garc´ıa, J . M.; Picard, J . P.; Dunogues, J .
Tetrahedron Lett. 1990, 31, 1921.
(39) These ketimines were prepared by mixing an excess of the
corresponding ketone (20 mL) and C,C-bis(trimethylsilyl)methylamine
(10 mmol) and stirring overnight either at room temperature (for 34a ,
34b, and 34d ) or at reflux temperature for (34c). On completion, the
excess of ketone was evaporated, and the imines were purified by
reduced pressure distillation.
(41) This method was inspired in the work by Mariano: Zhang, X.
M.; J ung, Y. S.; Mariano, P. S.; Fox, M. A.; Martin, P. S.; Merkert, J .
Tetrahedron Lett. 1993, 34, 5239.
(42) The acylation of the intermediate 3-amino â-lactam with Cbz-
Cl produced a side product which was not identified. On the other hand,
removal of the oxazolidinone ring after deprotection of the N-substitu-
ent caused complete destruction of the corresponding â-lactam.
(43) For N-deformylation methods, see: Georg, G. I.; He, P.; Kant,
J .; Wu, Z. J . J . Org. Chem. 1993, 58, 5771.

Synthesis of Homochiral 4,4-Disubstituted 2-Azetidinones
J . Org. Chem., Vol. 62, No. 7, 1997 2077
mmol) prepared as above and triethylamine (3.24 mL, 23.3
mmol) in dry CH2Cl2 under nitrogen at -78 °C. The resulting
mixture was stirred overnight under nitrogen, and the tem-
perature of the bath was allowed to rise from -78 °C to rt.
The mixture was diluted with CH2Cl2 (25 mL) and washed
with water (25 mL), 0.1 M HCl (25 mL), and saturated solution
of NaHCO3 (25 mL). The organic layer was dried over MgSO4,
and the solvent was evaporated under reduced pressure to give
the crude â-lactam, which was purified by column chroma-
tography (silica gel 200 mesh, EtOAc-hexanes (1:10) as
eluent).
Gen er a l P r oced u r e for th e P r ep a r a tion of r-Hyd r oxy
â-La cta m s 8. A suspension of the corresponding R-benzyloxy
â-lactam (10 mmol), NH4HCO2 (3.89 g, 61.7 mmol), and 10%
Pd on carbon (3.5 g) was refluxed with stirring in methanol
(20 mL) for 1 h. The mixture was filtered through Celite,
poured into H2O (50 mL), and extracted with CH2Cl2 (3 × 20
mL). The combined organic phases were dried over MgSO4
and evaporated to afford the corresponding R-hydroxy â-lac-
tams 8.
(3S,4S)-1-Ben zyl-4-[(1S)-1-[(ter t-b u t yld im et h ylsilyl)-
oxy]eth yl]-3-h yd r oxy-4-m eth yla zetid in -2-on e (8a ): yield,
97%; mp: 103-104 °C; [R]2D5 ) -3.5 (c ) 0.2, CH2Cl2); IR
(KBr) 3334, 1727 cm-1; 1H NMR (CDCl3, δ) 7.31-7.28 (m, 5H);
4.61 (d, 1H, J ) 15.3 Hz); 4.29 (s, 1H);4.29 (d, 1H, J ) 15.3
Hz); 4.20 (q, 1H, J ) 6.4 Hz); 1.20 (d, 3H, J ) 6.4 Hz); 1.13 (s,
9H). 13C NMR (CDCl3, δ) 169.5, 137.3, 128.6, 128.4, 128.3,
128.2, 127.5, 82.6, 72.3, 68.3, 44.7, 25.9, 18.8, 18.0, 17.5, -3.27,
-4.3. Anal. Calcd for C19H31NO3Si: C, 65.28; H, 8.96; N, 4.01.
Found: C, 65.40; H, 8.95; N, 3.99.
Con clu sion
Studies herein demonstrate the chemical and stereo-
chemical efficiency of the Staudinger reaction, relative
to the alternative ester-enolate imine approach, for the
construction of homochiral â-lactams with quaternary
stereogenic centers at the C(4) position. Consequently,
this work helps to close a gap in the field of â-lactam
synthesis by providing for the first time a wide variety
of structurally different C(4)-disubstituted â-lactams in
a single synthetic step. Most of these compounds can be
further transformed into other targets of biological inter-
est including amino acids, peptides, sugars, and hetero-
cycles involving a quaternary carbon and, thereby, an
open access to classes of compounds beyond those shown
here. We believe that this method can lead to strategies
for library generation that combine the case of solution
synthesis with the solid-supported synthetic methodology
recently highlighted by Gallop.45 Further studies will
address these possibilities.
Exp er im en ta l Section
Gen er a l Exp er im en ta l.46 Melting points were determined
with capillary apparatus and are uncorrected. Proton nuclear
magnetic resonance (300 MHz) spectra and 13C spectra (75
MHz) were recorded at room temperature for CDCl3 solutions,
unless otherwise stated. All chemical shifts are reported as δ
values (ppm) relative to residual CDCl3 δH (7.26 ppm) and
CDCl3 δC (77.0 ppm) as internal standards, respectively. Mass
spectra were obtained on a mass spectrometer (70 eV) using
GC-MS coupling (column: fused silica gel, 15 m, 0.25 mm, 0.25
µm phase SPB-5). Optical rotations were measured at 25 (
0.2 °C in methylene chloride unless otherwise stated. HPLC
analyses were performed on a preparative column (25 cm, 3.0
cm 7 µm phase Lichrosorb-Si60) with flow rates of 10 mL/min
and using a UV detector (254 nm). Flash chromatography was
executed with Merck Kiesegel 60 (230-400 mesh) using
mixtures of ethyl acetate or methylene chloride and hexane
as eluants. Hexane was dried and purified by distillation.
Tetrahydrofuran was distilled over sodium and benzophenone
(indicator). Methylene chloride and chloroform were shaken
with concentrated sulfuric acid, dried over potassium carbon-
ate, and distilled. Commercially available compounds were
used without further purification unless otherwise noted.
[(4S)-2-oxo-4-phenylxazolidin-3-yl]acetyl chloride was prepared
according to literature procedures.28a
Gen er a l P r oced u r e for th e P r ep a r a tion of Im in es 1-4.
The corresponding amine (15 mmol) and triethylamine (2.77
mL, 20 mmol) were successively added dropwise to a cooled
solution (-78 °C) of the corresponding ketone (10 mmol) in
dry CH2Cl2 (50 mL). TiCl4 (1 M solution in CH2Cl2, 5.0 mL)
was carefully added dropwise to the above mixture, maintain-
ing the temperature below -70 °C. The resulting suspension
was stirred at -78 °C for 90 min and then washed with cold
water (20 mL, ice-water), filtered through Celite, and washed
with cold NH4Cl (0.5 M, ice-water, 10 mL). The organic layer
containing the kenimine was separated, dried over MgSO4, and
used without further purification in the next step.
(3S,4S)-1-Ben zyl-4-[(1S)-1-[(ter t-b u t yld im et h ylsilyl)-
oxy]-2-m e t h ylp r op yl]-3-h yd r oxy-4-m e t h yla ze t id in -2-
on e (8b): yield, 90%; mp: 143 °C; [R]2D5 ) +25.0 (c ) 1,
CH2Cl2); IR (NaCl, film) 3267, 1750 cm-1
.
1H NMR (CDCl3,
δ) 7.32-7.25 (m, 5H); 4.80 (d, 1H, J ) 15.2 Hz); 4.38 (sb, 1H);
4.24 (d, 1H, J ) 15.2 Hz); 4.09 (d, 1H, J ) 2.4 Hz); 1.88-1.82
(m, 1H); 1.15 (s, 3H); 1.07 (d, 3H, J ) 4.2 Hz); 1.02 (s, 9H);
0.91 (d, 3H, J ) 7.2 Hz); 0.18 (s, 3H); 0.19 (s, 3H). 13C NMR
(CDCl3, δ ) 170.6, 138.0, 128.6, 128.4, 128.3, 128.4, 82.1, 80.1,
70.2, 45.6, 30.6, 26.5, 22.4, 18.6, 17.6, 17.3, -2.2, -3.9. Anal.
Calcd for C21H35NO3Si: C, 66.79; H, 9.36; N, 3.71. Found: C,
67.01; H, 9.35; N, 3.70.
(3S,4S)-1-Ben zyl-4-[(1S)-1-[(ter t-b u t yld im et h ylsilyl)-
oxy]-2-p h en ylet h yl]-3-h yd r oxy-4-m et h yla zet id in -2-on e
(8c): yield, 92%; mp: 152-153 °C. [R]2D5 ) +2.3 (c ) 1.0,
CH2Cl2); IR (NaCl, film) 3373, 1735 cm-1
.
1H NMR (CDCl3,
δ) 7.37-7.22 (m, 10H); 4.77 (d, 1H, J ) 4.6 Hz); 4.64 (d, 1H,
J ) 15.2 Hz); 4.53 (d, 1H, J ) 4.6 Hz); 4.47 (dd, 1H, J ) 3.7,
7.6 Hz); 4.03 (d, 1H, J ) 15.2 Hz); 3.13 (dd, 1H, J ) 3.7, 14.3
Hz); 2.70 (dd, 1H, J ) 7.6, 14.Hz); 1.23 (s, 3H); 0.95 (s, 9H);
0.06 (s, 3H); -0.53 (s, 3H). 13C NMR (CDCl3, δ) 169.5, 139.0,
137.5, 128.8, 128.7, 128.4, 128.4, 127.6, 126.4, 82.3, 78.5, 68.3,
45.2, 41.3, 26.1, 18.5, 18.1, -3.8, -4.7. Anal. Calcd for C25H35
-
NO3Si: C, 70.53; H, 8.30; N, 3.29. Found: C, 70.54; H, 8.31;
N, 3.29.
(3S,4S)-1-Ben zyl-4-[(1S)-1-[(ter t-b u t yld im et h ylsilyl)-
oxy]eth yl]-3-h yd r oxy-4-eth yla zetid in -2-on e (8d ): yield,
95%; syrup; [R]2D5 ) +6.0 (c ) 1.0, CH2Cl2); IR (NaCl, film)
3280, 1724 cm-1 1H NMR (CDCl3, δ) 7.36-7.26 (m, 10H); 4.88
.
(d, 1H, J ) 12.1 Hz); 4.71 (d, 1H, J ) 12.1 Hz); 4.67 (d, 1H, J
) 10.1 Hz); 4.32 (s, 1H); 4.28 (d, 1H, J ) 10.1 Hz); 4.27 (q,
1H, J ) 6.3 Hz); 1.67 (q, 2H, J ) 7.5 Hz); 1.23 (d, 3H, J ) 6.3
Hz); 0.92 (s, 9H); 0.57 (t, 3H, J ) 7.5 Hz); 0.09 (s, 3H); 0.04 (s,
3H). 13C NMR (CDCl3, δ) 168.6, 137.1, 137.0, 128.5, 128.4,
127.8, 127.4, 127.3, 80.1, 71.2, 70.1, 44.7, 44.8, 25.8, 24.5, 19.1,
17.9, 8.0, -2.8, -4.5. Anal. Calcd for C20H33NO3Si: C, 48.58;
H, 6.73; N, 2.83. Found: C, 48.73; H, 6.79; N, 2.86.
Gen er a l P r oced u r e for th e Syn th esis of r-Ben zyloxy
â-La cta m s 7 a n d 10. A solution of (benzyloxy)acetyl chloride
(2.05 mL, 13 mmol) in CH2Cl2 (15 mL) was added dropwise to
a stirred solution containing the corresponding imine (10
(44) For a more detailed experimental information on this subject,
see: Palomo, C.; Aizpurua, J . M.; Galarza, R.; Mielgo, A. J . Chem. Soc.,
Chem. Commun. 1996, 633.
(45) For a recent study documenting this aspect, see: Ruhland, B.;
Bhandari, A.; Gordon, E. M.; Gallop, M. A. J . Am. Chem. Soc. 1996,
118, 253.
(46) The authors have deposited the atomic coordinates for this
structure with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
(3R,4S)-1-Ben zyl-3-(ben zyloxy)-4-[(1R)-1,2-d ih yd r oxy-
eth yl]-4-m eth yla zetid in -2-on e (11). A solution of the â-lac-
tam 10 (3.81 g, 10 mmol) in THF (95 mL) and H2O (15 mL)
containing p-toluenesulfonic acid (0.65 g, 3.4 mmol) was
refluxed for 15 h, and then the organic solvent was evaporated
under reduced pressure. To the resulting mixture was added
saturated aqueous solution of NaHCO3 (30 mL) and extracted
three times with EtOAc (25 mL). The organic solvent was

2078 J . Org. Chem., Vol. 62, No. 7, 1997
Palomo et al.
dried over MgSO4 and evaporated under reduced pressure to
C23H38N2O3Si2: C, 61.85; H, 8.59; N, 6.27. Found: C, 61.76;
H, 8.41; N, 6.41.
give the title compound: yield, 85%; syrup; [R]2D5 ) +74.2 (c )
1, CH2Cl2); IR (NaCl, film) 3600-3200, 1730 cm-1 1H NMR
.
(3S)-1-[Bis(tr im eth ylsilyl)m eth yl]-4,4-d ip r op yl-3-[(4S)-
2-oxo-4-p h en yloxa zolid in -3-yl]a zetid in -2-on e (35c): yield,
70%; mp: 195-197 °C; [R]2D5 ) +65.5 (c ) 1.0, CH2Cl2); IR
(CDCl3, δ) 7.38-7.24 (m, 10H); 4.98 (d, 1H, J ) 11.6 Hz); 4.70
(d, 1H, J ) 11.6 Hz); 4.52 (d, 1H, J ) 15.2 Hz); 4.37 (d, 1H, J
) 15.2 Hz); 4.29 (s, 1H); 3.86 (dd, 1H, J ) 3.5, 7.2 Hz); 3.65
(dd, 1H, J ) 3.5, J ) 12.2 Hz); 3.53 (dd, 1H, J ) 7.2, J ) 12.2
Hz); 1.10 (s, 3H). 13C NMR (CDCl3, δ) 166.8, 136.8, 136.4,
128.7, 128.4, 128.2, 128.1, 127.7, 88.0, 74.0, 73.6, 66.4, 62.4,
44.4, 18.3. Anal. Calcd for C20H27NO4: C, 65.96; H, 7.28; N,
4.81. Found: C, 65.83; H, 7.23; N, 4.78.
(KBr) 1757, 1740 cm-1 1H NMR (CDCl3, δ) 7.39 (s, 5H); 5.05
.
(dd, 1H, J ) 6.1, 9.1 Hz); 4.67 (t, 1H, J ) 8.7 Hz); 4.18 (dd,
1H, J ) 6.0, 8.7 Hz); 3.92 (s, 1H); 2.03 (s, 1H); 1.40-1.24 (m,
8H), 1.0-0.88 (m, 6H), 0.13 (s, 9H); 0.05 (s, 9H). 13C NMR
(CDCl3, δ) 162.6, 158.2, 138.8, 129.3, 129.1, 127.8, 71.2, 68.0,
66.7, 59.7, 37.2, 34.7, 17.9, 17.5, 14.6, 14.3, 1.0, 0.4. Anal.
Calcd for C25H42N2O3Si2: C, 63.25; H, 8.94; N, 5.90. Found:
C, 63.02; H, 8.67; N, 6.13.
(3R,4S)-1-Ben zyl-3-(ben zyloxy)-4-ca r boxy-4-m eth yla ze-
tid in -2-on e (12). Sodium periodate (6.42 g, 30 mmol) was
added to a solution of the â-lactam 10 (3.41 g, 10 mmol) in
acetone (100 mL) and H2O (65 mL), and a white precipitate
was formed. Then, KMnO4 (0.79 g, 5 mmol) was added to the
reaction mixture, and an exothermic reaction occurred. After
stirring 20 min at room temperature, the reaction mixture was
cooled at 0 °C, and an aqueous solution of NaHSO3 (40%) was
added until decoloration. The mixture was extracted with
EtOAc (4 × 25 mL), and the extract dried over MgSO4 and
evaporated under reduced pressure to give the title compound
which was purified by column chromatography (silica gel 200
mesh, EtOAc-hexanes (1:2) as eluent): yield, 70%; syrup;
[R]2D5 ) +20.4 (c ) 1, CH2Cl2); IR (NaCl, film) 3380-3367,
(3S,4R)-1-[Bis(tr im eth ylsilyl)m eth yl]-4-eth yl-4-m eth yl-
3-[(4S)-2-oxo-4-ph en yloxazolidin -3-yl]azetidin -2-on e (35d):
yield, 80%; mp: 124-126 °C; [R]2D5 ) +59.5 (c ) 0.34, CH2-
Cl2); IR (KBr) 1758, 1750 cm-1
.
1H NMR (CDCl3, δ) 7.45-
7.40 (m, 5H); 5.22 (dd, 1H, J ) 6.8, 9.2 Hz); 4.71 (t, 1H, J )
9.0 Hz); 4.30 (dd, 1H, J ) 5.8, 8.8Hz); 4.20 (s, 1H); 1.85 (s,
1H); 1.41-1.28 (m, 2H), 1.31 (s, 3H); 0.89 (t, 3H); 0.18 (s, 9H);
0.06 (s, 9H). 13C NMR (CDCl3, δ) 162.0, 159.5, 139.4, 129.3,
129.1, 127.9, 71.5, 67.4, 65.4, 59.2, 35.3, 28.5, 19.8, 9.2, 0.9,
0.3. MS (m/ z, rel int) 271 (1.3), 198 (70), 73 (100), 59 (49), 45
(22). Anal. Calcd for C22H36N2O3Si2: C, 61.05; H, 8.40; N,
6.47. Found: C, 60.96; H, 8.20; N, 6.61.
1747 cm-1 1H NMR (CDCl3, δ) 7.37-7.27 (m, 10H); 6.30 (sb,
.
(3S,4R)-1-[Bis(tr im eth ylsilyl)m eth yl]-4-m eth yl-3-[(4S)-
2-oxo-4-ph en yloxazolidin -3-yl]-4-(2-ph en yleth yl)azetidin -
2-on e (35e): yield, 60%; mp: 120-123 °C; [R]2D5 ) +16.1 (c )
1H); 4.88 (d, 1H, J ) 15.2 Hz); 4.76 (d, 1H, J ) 11.6 Hz); 4.70
(d, 1H, J ) 11.6 Hz); 4.65 (s, 1H); 4.14 (d, 1H, J ) 15.2 Hz);
1.29 (s, 3H). 13C NMR (CDCl3, δ) 175.2, 165.7, 136.2, 135.6,
128.7, 128.6, 128.5, 128.1, 127.9, 89.3, 73.4, 44.6, 68.0, 44.7,
19.8. Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.30.
Found: C, 69.84; H, 6.02; N, 4.22.
1.0, CH2Cl2); IR (KBr) 1759, 1751 cm-1 1H NMR (CDCl3, δ)
.
7.37-7.12 (m, 10H); 5.22 (dd, 1H, J ) 8.2, 6.3 Hz); 4.70 (t,
1H, J ) 8.9 Hz); 4.25 (s, 1H); 4.22 (dd, 1H, J ) 8.9, 6.2 Hz);
2.68-2.60 (m, 2H); 1.87 (s, 1H); 1.71-1.57 (m, 2H); 1.42 (s, 3H);
0.17 (s, 9H); -0.02 (s, 9H). 13C NMR (CDCl3, δ) 162.0, 159.6,
141.2, 139.9, 129.2, 128.9, 128.5, 128.2, 128.0, 126.0, 71.8, 67.8,
64.8, 59.1, 36.3, 35.5, 30.2, 20.5, 0.9, 0.4. Anal. Calcd for
C28H40N2O3Si2: C, 66.08; H, 7.94; N, 5.50. Found: C, 66.15;
H, 8.01; N, 5.36.
Gen er a l P r oced u r e for th e Syn th esis of â-La cta m s 21,
22, a n d 35. Oxalyl chloride (1.30 mL, 15 mmol) was added
carefully to a stirred solution of the corresponding â-(dimeth-
ylphenylsilyl)alkanoic acid or (4S)-(2-oxo-4-phenyl-3-oxazo-
lidinyl)acetic acid (12 mmol) in CH2Cl2 (36 mL) cooled at 0
°C, followed by slow addition of anhydrous DMF (0.05 mL,
cat.). After 1 h stirring at rt, the mixture was evaporated at
reduced pressure to afford the corresponding acid chloride.
This compound was redissolved in CH2Cl2 (15 mL) and added
dropwise to a mixture containing 4 Å molecular sieves (2 g),
the corresponding imine 18 or 34 (10 mmol), and triethylamine
(3.32 mL, 24 mmol) in methylene chloride (25 mL) at 0 °C.
The mixture was refluxed overnight under nitrogen, the
molecular sieves were filtered off, and the filtrate was washed
successively with 1 M HCl (25 mL), saturated solution of
NaHCO3 (25 mL), and water (25 mL). The organic layer was
dried over MgSO4, and the solvent was evaporated under
reduced pressure to give the crude â-lactam, which was
purified by column chromatography (silica gel 200 mesh,
EtOAc-hexanes (1:8) as eluent). Analytical samples were
available by crystallization from hexanes or by preparative
HPLC.
(3S,4R)-1-[Bis(tr im eth ylsilyl)m eth yl]-4-m eth yl-3-[(4S)-
2-oxo-4-p h en yloxa zolid in -3-yl]a zetid in -2-on e (35f): yield,
49%; mp: 142-144 °C; [R]2D5 ) +91.1 (c ) 1.0, CH2Cl2); IR
(KBr) 1740 cm-1 1H NMR (CDCl3, δ) 7.43 (m, 5H); 5.08 (dd,
.
1H, J ) 6.2, 8.9 Hz); 4.73 (t, 1H, J ) 8.9 Hz); 4.52 (d, 1H, J )
4.8 Hz); 4.23 (dd, 1H, J ) 6.2, 9.0 Hz); 3.67 (m, 1H); 2.12 (s,
1H); 1.10 (d, 3H, J ) 6.3 Hz); 0.82 (s, 9H); 0.04 (s, 9H). 13C
NMR (CDCl3, δ) 162.3, 158.4, 138.5, 129.1, 129.0, 127.6, 71.2,
60.4, 59.4, 56.7, 38.0, 13.8, -0.1, -0.2. MS (m/ z, rel int) 390
(3.2), 204 (21), 104 (71), 73 (100). Anal. Calcd for C20H32N2O3-
Si2: C, 59.36; H, 7.97; N, 6.92. Found: C, 59.02; H, 8.09; N,
6.98.
(3S,4R)-1-[Bis(tr im eth ylsilyl)m eth yl]-4-m eth yl-3-[(4S)-
2-oxo-4-p h en yloxa zolid in -3-yl]a zetid in -2-on e (35g): yield,
49%; oil; [R]2D5 ) +30.2 (c ) 1.0, CH2Cl2); IR (NaCl, film) 1743,
1737 cm-1 1H NMR (CDCl3, δ) 7.38-7.14 (m, 10H); 4.94 (m,
.
1H); 4.65 (t, 1H, J ) 8.8 Hz); 4.58 (db, 1H); 4.18 (dd, 1H, J )
8.8, 5.9Hz); 3.50 (m, 1H); 2.64 (t, 2H, J ) 7.8 Hz); 2.04 (s, 1H);
1.85-1.50 (m, 2H); 0.05 (s, 9H); 0.04 (s, 9H). 13C NMR (CDCl3,
δ) 162.7, 158.4, 140.7, 138.6, 129.2, 129.0, 128.4, 128.1, 127.5,
126.0, 71.1, 60.5, 59.2, 38.6, 32.1, 29.8, -0.1, -0.2. MS (m/ z,
rel int) 219 (36), 73 (100), 59 (35). Anal. Calcd for C27H38N2O3-
Si2: C, 65.54; H, 7.74; N, 5.66. Found: C, 65.23; H, 7.99; N,
5.63.
(3S)-1-[Bis(tr im eth ylsilyl)m eth yl]-4,4-d im eth yl-3-[(4S)-
2-oxo-4-p h en yloxa zolid in -3-yl]a zetid in -2-on e (35a ): yield,
70%; mp: 101-103 °C; [R]2D5 ) +55.4 (c ) 1.0, CH2Cl2); IR
(KBr) 1737 cm-1 1H NMR (CDCl3, δ) 7.44-7.34 (m, 5H); 5.12
.
(dd, 1H, J ) 6.0, 9.1 Hz); 4.71 (t, 1H, J ) 9.1 Hz); 4.25 (dd,
1H, J ) 6.0, 9.1 Hz); 4.10 (s, 1H); 1.78 (s, 1H); 1.30 (s, 3H);
1.04 (s, 3H); 0.12 (s, 9H); -0.06 (s, 9H). 13C NMR (CDCl3, δ)
161.4, 158.3, 138.7, 128.9, 128.7, 127.7, 71.3, 66.7, 61.8, 58.9,
34.7, 23.3, 21.9, 0.43, -0.1. MS (m/ z, rel int) 418 (0.5), 403
(33), 345 (40), 345 (62), 104 (63), 73 (100). Anal. Calcd for
C21H34N2O3Si2: C, 60.24; H, 8.18; N, 6.69. Found: C, 60.22;
H, 8.11; N, 6.74.
Gen er a l P r oced u r e for th e Dep r otection of N-[Bis-
(tr im eth ylsilyl)m eth yl] â-La cta m s 35 a n d 39: Meth od A:
To a solution of the corresponding â-lactam (5 mmol) in dry
MeOH (40 mL) or acetonitrile (30 mL)/water (12.5 mL) was
added cerium(IV) ammonium nitrate (10.96 g, 20 mmol) at
room temperature, and the suspension was stirred at the same
temperature for 2-3 h. The reaction mixture was taken up
over water (50 mL) and extracted with EtOAc (3 × 80 mL).
The organic layer was washed successively with aqueous
NaHCO3 (100 mL, saturated solution), aqueous NaHSO3 (3 ×
50 mL, 40%), aqueous NaHCO3 (100 mL, saturated solution),
and aqueous NaCl (100 mL, saturated solution). Drying and
evaporation of solvents yielded fairly pure N-formyl â-lactams
(e.g: 37) which was dissolved in a mixture of acetone (8.5 mL),
(3S)-1-[Bis(t r im et h ylsilyl)m et h yl]-4,4-d iet h yl-3-[(4S)-
2-oxo-4-p h en yloxa zolid in -3-yl]a zetid in -2-on e (35b): yield,
69%; mp: 101-102 °C; [R]2D5 ) +57.1 (c ) 1.0, CH2Cl2); IR
(KBr) 1759, 1738 cm-1 1H NMR (CDCl3, δ) 7.39 (s, 5H); 4.99
.
(dd, 1H, J ) 6.7, 9.0 Hz); 4.67 (t, 1H, J ) 8.8Hz); 4.16 (dd, 1H,
J ) 6.5Hz, J ) 8.7Hz); 3.83 (s, 1H); 2.06 (s, 1H); 1.88-1.39
(m, 2H), 0.98-0.84 (m, 2H), 0.13 (s, 9H); 0.09 (s, 9H). 13C NMR
(CDCl3, δ) 162.5, 158.2, 138.4, 129.4, 129.2, 127.6, 71.7, 68.7,
66.2, 60.0, 37.4, 26.9, 24.2, 9.2, 8.9, 1.0, 0.4 . Anal. Calcd for

Synthesis of Homochiral 4,4-Disubstituted 2-Azetidinones
J . Org. Chem., Vol. 62, No. 7, 1997 2079
aqueous NaHCO3 (8.5 mL, saturated solution), and Na2CO3
(0.14 g, 0.5 mmol). After stirring at room temperature for 2
h, the suspension was filtered through a pad of silica gel and
washed with acetone (25 mL) and the resulting solution
evaporated under reduced pressure to afford N-H-â-lactams
38 or 40 which were purified by crystallization in EtOAc/
hexanes. (3S)-3-[(Ben zyloxyca r bon yl)a m in o]-4,4-d im eth -
suspension was stirred at reflux temperature for 3 h. Workup
as in method A afforded pure N-H-â-lactams 38.
Ack n ow led gm en t. This work was supported by the
Ministry of Education of the Spanish Government
(Project: SAF: 95/0749), Gobierno Vasco (Project: PI
95/93) and in part by Basque Country University
(UPV: 170.215-EB147/94).
yla zetid in -2-on e (40): yield, 70%; mp: 118-119 °C; [R]D25
+38.9 (c ) 1.0, CH2Cl2); IR (KBr) 3340, 3218, 1721 cm-1, 1696
cm-1 1H NMR (CDCl3, δ) 7.31 (s, 5H); 6.55 (s, 1H); 6.24 (d,
)
Su p p or tin g In for m a tion Ava ila ble: A listing of physical
and spectroscopic data of compounds 5, 6, 7a -d , 10, 21a ,b,
22a ,b, 26a -c, 28, 29, 32a -c, 39, as well as the X-ray
crystallographic data of 22b and 37d (9 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
.
1H, J ) 8.1 Hz); 5.07 (s, 2H); 4.56 (d, 1H); 1.23 (s, 3H); 1.22
(s, 3H). 13C NMR (CDCl3, δ) 166.7, 156.0, 136.0, 128.4, 128.1,
127.9, 67.0, 65.7, 58.4, 26.2, 22.3. MS (m/ z, rel int) 205 (3),
91 (100), 58 (77). Anal. Calcd for C13H16N2O3: C, 62.88; H,
6.51; N, 11.28. Found: C, 63.03; H, 6.59; N, 11.35.
Meth od B: To a solution of the corresponding â-lactam (5
mmol) in dry MeOH (40 mL) was added cerium(IV) ammonium
nitrate (10.96 g, 20 mmol) at room temperature, and the
J O962017Z