A study on the asymmetric synthesis of β-lactams through double stereodifferentiating cycloaddition reactions

Article abstract of DOI:10.1021/jo9612180

The cycloaddition reaction of chiral aminoketenes, generated from their corresponding acid chlorides and triethylamine, with chiral imines is evaluated as the most direct approach for the construction of cis-β-lactams with the absolute stereochemistry at the C₃ and C₄ positions being controlled by the ketene partner, independently of the absolute stereochemistry of the imine component.

Full text of DOI:10.1021/jo9612180

9186
J . Org. Chem. 1996, 61, 9186-9195
A Stu d y on th e Asym m etr ic Syn th esis of â-La cta m s th r ou gh
Dou ble Ster eod iffer en tia tin g Cycloa d d ition Rea ction s
Claudio Palomo,*,† J esu´s M. Aizpurua,† Antonia Mielgo,† and Anthony Linden‡
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad del Pais Vasco, Apdo 1072,
20080 San Sebastia´n, Spain, and Organisch-chemisches Institut der Universita¨t
Zu¨rich,Winterthurerstrasse 190, CH-8057 Zu¨rich, Switzerland
Received J une 27, 1996X
The cycloaddition reaction of chiral aminoketenes, generated from their corresponding acid chlorides
and triethylamine, with chiral imines is evaluated as the most direct approach for the construction
of cis-â-lactams with the absolute stereochemistry at the C3 and C4 positions being controlled by
the ketene partner, independently of the absolute stereochemistry of the imine component.
The â-lactam skeleton is the key structural element
induction is entirely dictated by the configuration of the
starting ketene.6g On the other hand, impressive results
have also been obtained in the cycloaddition reaction of
achiral ketenes with chiral imines, especially when the
chirality is induced by the aldehyde component.7 By this
means, virtually complete control of the level of reaction
diastereoselection has been achieved using imines de-
rived from both 1(S)-8 and 1(R)-glyceraldehyde acetonide9
(eq 2). Subsequent to these findings, work in this
laboratory and others has also documented the utility of
O-protected R-hydroxy-substituted acetaldehydes as ef-
fective tools for the asymmetric synthesis of â-lactams.10
However, the question of the stereochemical outcome
when a homochiral ketene reacts with homochiral alde-
of the most widely employed class of antibacterial agents,
the â-lactam antibiotics.1 As a consequence, a plethora
of methods for the production of â-lactams are now
available, and the topic has been reviewed on more than
one occassion.2 In particular, the [2 + 2] cycloaddition
reaction of ketenes to imines, known as the Staudinger
reaction,3 has acquired central importance for the asym-
metric construction of the azetidinone ring, from both
academic and industrial standpoints.4,5 Over the past
years, this reaction has been extensively developed by
using a combination of either chiral ketenes and achiral
imines or achiral ketenes and chiral imines, generally
providing good yields and excellent diastereoselectivity.5
One example is the cycloaddition reaction of Evans-
Sjo¨gren ketenes, generated from chiral oxazolidinylacetic
acid chlorides and triethylamine, with achiral imines to
form optically active â-lactams with high levels of asym-
metric induction, typically g96% de.6 This exceptional
quality of stereochemical control imparted by the oxazo-
lidinone moiety has also been demonstrated in the
reaction of (4(S)-phenyloxazolidinyl)ketene with imines
derived from achiral aldehydes and either (R)- or (S)-R-
amino esters (eq 1) in which the sense of the asymmetric
(6) (a) Evans, D. A.; Sjo¨gren, E. B. Tetrahedron Lett. 1985, 27, 3783;
1985, 26, 3787. (b) Eudalay, J . A.; Hornback, W. J .; J ohnson, R. J .;
J ordan, C. L.; Munroe, J . E.; Wright, W. E.; Wu, C. Y. E. In Recent
Advances in the Chemistry of â-Lactam Antibiotics; Bentley, P. H.,
Southgate, R., Eds.; Royal Society of Chemistry: London, 1989; p 333.
(c) Muller, M.; Bur, D.; Tschamber, T.; Streith, J . Helv. Chim. Acta
1991, 74, 767. (d) Boger, D. L.; Myers, J . B., J r. J . Org. Chem. 1991,
56, 5385. (e) Palomo, C.; Aizpurua, J . M.; Miranda, J . I.; Mielgo, A.;
Odriozola, J . M. Tetrahedron Lett. 1993, 34, 6325. (f) Holton, R. A.;
Liu, J . H. Bioorg. Med. Chem. Lett. 1993, 3, 2475. (g) Ojima, I. In The
Organic Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: New York,
1993; p 197. (h) 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, 35, 1239. For a new chiral aminoketene
precursor, see: (i) Duczek, W.; J a¨hnisch, K.; Kunath, A.; Reck, G.;
Winter, G.; Schulz, B. Liebigs Ann. Chem. 1992, 781. From aminocar-
bene complexes, see: (j) Schwindt, H. A.; Miller, J . R.; Hegedus, L. S.
J . Organomet. Chem. 1991, 413, 143.
(7) In general, the level of asymmetric induction achieved with
imines derived from achiral aldehydes and chiral amines is lower than
that for those derived from the ketene or aldehyde component. For
example, see: (a) Georg, G. I.; Wu, Z. Tetrahedron Lett. 1994, 35, 381.
For some exceptions, see: (b) Tenneson, S. M.; Belleau, B. Can. J .
Chem. 1980, 58, 1605. (c) Bose, A. K.; Manhas, M. S.; van der Veen, J .
M.; Bari, S. S.; Wagle, D. R. Tetrahedron 1992, 48, 4831. (c) Barton,
D. H. R.; Gateau-Olesker, A.; Anaya-Mateos, J .; Cle´ophax, J .; Ge´ro, S.
D.; Chiaroni, A.; Riche, C. J . Chem. Soc., Perkin Trans. 1 1990, 3211.
(d) Farina, V.; Hauck, S. I.; Walker, D. G. Synlett 1992, 761.
(8) Hubschwerlen, C.; Schmid, G. Helv. Chim. Acta 1983, 66, 2206.
(9) (a) 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. (b) Welch, J . T.; Araki, K.; Kawecki, R.;
Wichtowski, J . A. J . Org. Chem. 1993, 58, 2454.
† Departamento de Qu´ımica Orga´nica.
‡ Organisch-chemisches Institut. Author to whom correspondence
regarding the X-ray crystallographic determination should be ad-
dressed.
X Abstract published in Advance ACS Abstracts, November 15, 1996.
(1) For some reviews on â-lactam antibiotics, see: (a) Du¨rkheimer,
W.; Blumbach, J .; Lattrell, R.; Scheunemann, K. H. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 180. (b) Chemistry and Biology of â-Lactam
Antibiotics, Vols. 1-3; Morin, R. B., Gorman, M., Eds.; Academic
Press: New York, 1982. (c) Southgate, R.; Branch, C.; Coulton, S.;
Hunt, E. In Recent Progress in the Chemical Synthesis of Antibiotics
and Related Microbial Products; Lukacs, G., Ed.; Springer-Verlag:
Berlin, 1993; Vol. 2, p 621. (d) Southgate, R. Contemp. Org. Synth.
1994, 1, 417.
(2) For comprehensive general reviews, see: (a) Koppel, G. A. In
Small Ring Heterocycles; Hasner, A., Ed.; Wiley: New York, 1983; Vol.
42, p 219. (b) Backes, J . In Houben-Weyl, Methoden der Organischem
Chemie; Muller, E., Bayer, O., Eds; Thieme: Stuttgart, 1991; Band
E16B, p 31.
(3) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51.
(4) For recent reviews on asymmetric synthesis of â-lactams, see:
(a) Thomas, R. C. In Recent Progress in The Chemical Synthesis of
Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer-Verlag: Berlin, 1990;
p 533. (b) Ternansky, R. J .; Morin, J . M., J r. In The Organic Chemistry
of â-Lactams; Georg, G. I., Ed.; VCH: New York, 1993; p 257. (c)
Ghosez, L.; Marchand-Brynaert, S. In Comprehensive Organic Syn-
thesis; Trost, B., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p
85.
(5) For reviews on the asymmetric Staudinger reaction, see: (a)
Cooper, R. D. G.; Daugherty, B. W.; Boyd, D. B. Pure Appl. Chem. 1987,
59, 485. (b) Van der Steen, F. H.; VanKoten, G. Tetrahedron 1991, 47,
5703. (c) Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of
â-Lactams; Georg, G. I., Ed.; VCH: New York, 1993; p 295.
(10) (a) Palomo, C.; Coss´ıo, F. P.; Ontoria, J . M.; Odriozola, J . M.
Tetrahedron Lett. 1991, 32, 3105. (b) Palomo, C.; Aizpurua, J . M.;
Urchegui, R.; Garc´ıa, J . M. J . Org. Chem. 1993, 58, 1646. (c) Brown,
A. D.; Colvin, E. W. Tetrahedron Lett. 1991, 32, 5187. (d) Kobayashi,
Y.; Takemoto, T.; Kamijo, T.; Harada, H.; Ito, Y.; Terashima, S.
Tetrahedron 1992, 48, 1853. For related reactions using R,â-epoxy
imines, see: (e) Evans, D. A.; Williams, M. J . Tetrahedron Lett. 1988,
29, 5065. (f) Frazier, J . W.; Staszak, M. A.; Weigel, L. O. Tetrahedron
Lett. 1992, 33, 857. For related reactions involving sugar aldehyde-
derived imines, see: (g) Saito, S.; Ishikawa, T.; Morikawe, T. Synlett
1993, 139. (h) Kaluza, Z.; Manhas, M. S.; Barakat, K. J .; Bose, A. K.
Bioorg. Med. Chem. Lett. 1993, 3, 2357.
S0022-3263(96)01218-2 CCC: $12.00 © 1996 American Chemical Society

Asymmetric Synthesis of â-Lactams
J . Org. Chem., Vol. 61, No. 26, 1996 9187
hyde-derived imines still remains unclear.11 In particu-
lar, by understanding the stereochemical control ele-
ments involved in such processes, it would be possible to
delineate a convergent access to â-lactams with the
stereochemistry being controlled by the ketene partner12
(eq 3). In particular, diastereomeric â-lactams similar
to those provided by reactions in eq 2, but with the same
stereochemistry at the exocyclic stereogenic center, would
be accessible for the first time. As a consequence, the
approach would extend the scope of â-lactam chemistry1
and the chemistry employing â-lactams as the synthetic
building blocks of non-â-lactam products.13 Herein we
disclose our studies addressing these issues.
F igu r e 1.
Sch em e 1a
a
Reagents and conditions: (a) NaH, THF, BrCH2CO2Me, 2 h,
0 °C, then NaOH, H2O, THF, 2 h, rt; (b) ClCOCOCl, CH2Cl2, DMF
cat., 1 h, rt.
Resu lts a n d Discu ssion
For the study we elected to use the Evans-Sjo¨gren
ketenes derived from the acid chlorides 1 and 2 and the
imines 3, 4, and 5 as representative examples (Figure
1). In all cases, the ketenes were generated by adding
triethylamine to a solution of the corresponding oxazo-
lidinylacetic acid chlorides 2 in methylene chloride at -78
°C (Scheme 1), the respective imines were then added to
the preformed ketenes, and the mixture was allowed to
react for 2 h at 0 °C and then at room temperature
overnight. These reactions were selected for development
in view of the existing precedents concerning the syn-
thesis of O-2-isocephems,14 a particular class of nuclear
analogues of cephalosporins with promising therapeutic
activity. In other terms, the success of our hypothesis
would imply a single-step access to monocylic â-lactams
as precursors of the bicyclic structures depicted in Figure
2. We have adopted the terminology “matched-mis-
matched” introduced by Masamune15 and, accordingly,
F igu r e 2.
when both chiral reagents creating two new stereocenters
(x,y) display the same or opposite induction sense, the
interactions are termed “x,y-matched” and “x,y-mis-
matched”, respectively.
Rea ction of Ch ir a l Am in ok eten es w ith Ch ir a l
Im in es Der ived fr om Ch ir a l r-Oxy Ald eh yd es a n d
Ach ir a l Am in es. Th e 3,4-Ma tch ed a n d 3,4-Mis-
m a tch ed Ca ses. Although the concept of double asym-
metric induction has been extensively applied to a wide
array of important reactions, hitherto the interaction of
two chiral reactants in [2 + 2] cycloaddition reactions
involving ketenes remains an unexplored area.15,16 There-
(11) For a recent paper dealing with the reaction of achiral ketenes
with imines derived from chiral aldehydes and chiral amines, see: (a)
Niu, C.; Miller, M. J . Tetrahedron Lett. 1995, 36, 497. (b) Niu, C.;
Petterson, T.; Miller, M. J . J . Org. Chem. 1996, 61, 1014.
(12) For details on the mechanism of the Staudinger reaction, see:
(a) ref 4a. (b) Hegedus, L. S.; Montgomery, J .; Narukawa, Y.; Snustad,
D. C. J . Am. Chem. Soc. 1991, 113, 5784. (b) Sordo, J . A.; Gonza´lez,
J .; Sordo, T. L. J . Am. Chem. Soc. 1992, 114, 6249. (c) Palomo, C.;
Coss´ıo, F. P.; Cuevas, C.; Lecea, B.; Mielgo, A.; Roman, P.; Luque, A.;
Mart´ınez-Ripoll, M. J . Am. Chem. Soc. 1992, 114, 9360. (d) Coss´ıo, F.
P.; Ugalde, J . M.; Lo´pez, X.; Lecea, B.; Palomo, C. J . Am. Chem. Soc.
1993, 115, 995. (e) Yamabe, S.; Minato, T.; Osamura, Y. J . Chem. Soc.,
Chem. Commun. 1993, 450.
(14) For representative synthetic strategies to O-2-isocephems,
see: (a) Tenneson, S. M.; Belleu, B. Can. J . Chem. 1980, 58, 1605. (b)
Doyle, T. W.; Douglas, J . L.; Bellau, B.; Conway, T. T.; Ferrari, C. F.;
Horning, D. E.; Lim, G.; Luh, B. Y.; Martel, A.; Menard, M.; Morris,
M. L.; Misiek, M. Can. J . Chem. 1980, 58, 2508. (c) Hakimelahi, G. H.
Helv. Chim. Acta 1982, 65, 1378. (d) Hrytsak, M.; Durst, T. Heterocycles
1987, 26, 2393. (e) Mastarelz, H.; Vinet, V. J . Chem. Soc., Chem.
Commun. 1987, 1283. (f) Nitta, H.; Hatanaka, M.; Ishimura, T. J .
Chem. Soc., Chem. Commun. 1987, 51. (g) Nitta, H.; Hatanaka, M.;
Ueda, I. J . Chem. Soc., Perkin Trans. 1 1990, 432. (h) Tsubouchi, H.;
Tsuji, K.; Yasumura, K.; Tada, N.; Nishitami, S.; Minamikawa, J .;
Ishikawa, H. Tetrahedron: Asymmetry 1994, 5, 441. See also ref 11b
and references therein.
(13) For detailed information on this topic, see: (a) Manhas, M. S.;
Wagle, D. R.; Chiang, J .; Bose, A. K. Heterocycles 1988, 27, 1755. (b)
Ojima, I. Acc. Chem. Res. 1995, 383. (c) Hesse, M. In Ring enlargement
in Organic Chemistry; VCH: Weinheim, 1991. (d) Hegedus, L. S. Acc.
Chem. Res. 1995, 28, 299.
(15) Masamune, S.; Choy, W.; Peterson, J . S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
(16) For
a study on double asymmetric induction in the ester
enolate-imine condensation, see: Annunziata, R.; Benaglia, M.;
Chiovato, A.; Cinquini, M.; Cozzi, F. Tetrahedron 1995, 51, 10025.

9188 J . Org. Chem., Vol. 61, No. 26, 1996
Palomo et al.
Sch em e 2a
Sch em e 4a
a
Reagents and conditions: (a) NEt3, CH2Cl2, -78 °C f rt, 20
a
h; (b) p-TosOH, THF, H2O; (c) NaIO4, Me2CO, H2O; (d) NaBH4,
Reagents and conditions: (a) NEt3, CH2Cl2, -78 °C f rt, 20
MeOH.
h; (b) p-TosOH, THF, H2O; (c) NaIO4, Me2CO, H2O; (d) NaBH4,
MeOH.
Sch em e 5a
Sch em e 3a
a
Reagents and conditions: (a) 2, NEt3, CH2Cl2, -78 °C f rt,
20 h; (b) nBu4F, THF, then (Cl3CO)2CO, DMSO, NEt3, 70-75%.
of induction of the ketene derived from 2a with the imine
3. In this case, both chiral templates were mismatched
and the result was the formation of a mixture of â-lac-
tams 19 and 20 in a 40:60 ratio, respectively, as deter-
a
Reagents and conditions: (a) 2, NEt3, CH2Cl2, -78 °C f rt,
20 h; (b) nBu4NF, THF; (c) (Cl3CO)2CO/DMSO, NEt3, CH2Cl2, -78
°C.
1
mined by H NMR (Scheme 4). The absolute configura-
tion of these adducts was established again by their
conversion into the corresponding 4-hydroxymethyl de-
rivatives 21 and 22, respectively. Compound 22 had been
previously obtained by an independent route,12c and 21
was identified as the enantiomer of 12. With this result
in hand, we subjected imine 6 to treatment with 2a and
triethylamine (Scheme 5), and the stereochemical result
was the same as that achieved with the imine 3; namely,
a mixture of â-lactams 23a and 24a (52% yield) was
produced in a 40:60 ratio, respectively. A somewhat
better stereochemical outcome was attained when the
imine 7 was employed in this reaction to give â-lactams
25a and 26a (67% yield) in a 30:70 ratio, respectively.
fore, our study began with the simplest case, that is the
reaction of the ketene generated from 1 as above with
the imine 3 (Scheme 2) in which the sense of asymmetric
induction of both chiral templates was matched, and as
a result, only one â-lactam adduct should be expected.
In effect, this was the case and the absolute configuration
at the C3 and C4 positions of the resulting â-lactam
product 10 was unequivocally established by removal of
the acetonide protecting group, followed by oxidative
cleavage of the resulting glycol and subsequent reduction
of the 4-formyl â-lactam 11 into the 4-hydroxymethyl
derivative 12, whose absolute configuration has been
previously established.6d Similarly (Scheme 3), the imine
4 upon exposure to acid chlorides 2a , 2b, and 2c and
triethylamine led to the formation of â-lactams 13a , 13b,
and 13c in 56%, 58%, and 83% yields, respectively, as
single diastereomers. The same stereochemical result
was produced when 2a reacted with the imine 5 to
produce the cycloadduct 14a in 65% isolated yield. For
reasons which will be outlined later, each â-lactam 13a -c
and 14a was subjected to O-desilylation to give 15a -c
and 16a , respectively. These â-lactam products, upon
Swern oxidation, afforded the corresponding ketones
17a -c and 18a .
Each pair of diastereomers was separated by column
chromatography or by preparative HPLC and correlated
with those obtained in the matched case, vide supra. As
shown in Scheme 5, compounds 23a and 25a , upon
elaboration of the C4 substituent, led to the carbonyl
derivatives 17a and 18a , identical in all respects to those
previously obtained from 13a and 14a (Scheme 3),
respectively. Moreover, since adducts 27a and 28a
showed identical coupling constants (J cisC3-C4 ≈ 5 Hz) to
those of 17a and 18a , their absolute stereochemistry
should be as depicted.
The next step of our study was to confront the sense
In view of the recent methods for recovering6e,f and/or

Asymmetric Synthesis of â-Lactams
J . Org. Chem., Vol. 61, No. 26, 1996 9189
cleaving17 oxazolidinone chiral auxiliaries, we next evalu-
ated the behavior of ketenes derived from 2b and 2c in
such a cycloaddition process with the aim of establishing
whether bulkier groups at the C3 position of the oxazo-
lidinone moiety might exert some influence in directing
the stereochemical course of the reaction.18 In an effort
to verify this argument, we subjected imine 6 to treat-
ment with 2b and 2c under the same conditions as above.
In the first case, a mixture of cycloadducts 23b and 24b
(52% yield) was produced in a 75:25 ratio, thus indicating
that, indeed, by increasing the size of the substituent on
the ketene partner, it is possible to control the reaction
diastereoselectivity. Likewise, the imine 7, upon treat-
ment with 2b, gave 25b/26b (63% yield) in a 70:30 ratio,
respectively. Surprisingly, when 2c was used, derived
from the bulkier amino acid tert-leucine and imines 6 and
7, only the anti-Evans â-lactams 24c (80% yield) and 26c
(82% yield) were produced without traces of the corre-
sponding diastereomeric products.
Sch em e 6a
a
Reagents and conditions: (a) NaH, THF, BrCH2CO2Me, 2 h,
0 °C, then NaOH, H2O, THF, 2 h, rt; (b) ClCOCOCl, CH2Cl2, DMF
cat., 1 h, rt.
Sch em e 7a
The absolute configurations of 23b and 25b were
established by chemical correlation with the correspond-
ing ketones 17b and 18b, which were identical to those
obtained from the respective combinations in a matched
relationship (see Scheme 3). As expected, adducts 24b
and 26b upon desilylation and subsequent oxidation gave
the corresponding diastereomeric ketones 27b and 28b,
respectively. Finally, compounds 23b and 24c were
submitted to single-crystal X-ray analyses to further
confirm unambiguously the sense of asymmetric induc-
tion observed for these reactions.19
The imidazolidinone 29 has proven to be useful for
asymmetric transformations,20 including [4 + 2] cyclo-
additions.21 Therefore, we also examined its behavior in
[2 + 2] cycloadditions. The primary aim was to evaluate
whether an additional stereogenic center on the chiral
inductor could influence the stereochemical outcome of
the cycloaddition. First, the corresponding acid chloride
31 was prepared (Scheme 6) from the acid 30 and
a
Reagents and conditions: (a) 6, NEt3, CH2Cl2, -78 °C f rt,
20 h; (b) 4 or 5, NEt3, CH2CL2, -78 °C f rt, 20 h.
subjected to treatment with the imine 6. As Scheme 7
illustrates, the result was, as to be expected by the
matched relationship between both components, the
formation of the â-lactam 32 whose relative configuration
was determined by X-ray analysis.22 Once we had
established that the sense of asymmetric induction
exerted by this imidazolidinone inductor was the same
as that observed for the above oxazolidinone derivatives,
we investigated the reaction of 31 with imines 4 and 5
in which each reactant was in a mismatched relationship.
While in the latter case a mixture of â-lactams 35/36 in
a 70:30 ratio was produced,23 in the former case only the
â-lactam product 33, with stereochemistry dictated by
the ketene partner, was obtained in a de higher than
95%.
(17) Fisher, J . W.; Dunigan, J . M.; Hatfield, L. D.; Hoying, R. C.;
Ray, J . E.; Thomas, K. L. Tetrahedron Lett. 1993, 34, 4755.
(18) A semiempirical SCF-MO AM1 study carried out by us indicated
that the stereochemistry observed for the reaction of chiral Evans-
Sjo¨gren ketenes with achiral imines, and particularly those involving
the (trimethylsilyl)methyl moiety, is governed by the relative orienta-
tion adopted by the phenyl group in the corresponding transition state.
While our theoretical work was in progress, an anticipated paper by
Cossio from this laboratory documented the same observation, see:
Coss´ıo, F. P.; Arrieta, A.; Lecea, B.; Ugalde, J . M. J . Am. Chem. Soc.
1994, 116, 2085.
(19) Crystal data for compound 23b: C24H38N2O4Si, Mr ) 446.65,
triclinic, space group P1, a ) 14.258(4), b ) 15.172(3), and c )
6.256(1) Å, R ) 93.40(2), â ) 95.45(2), and γ ) 71.70(2)°, V )
1278.5(5) Å-3, Z ) 2, Dc ) 1.160 g cm-3, T ) -100 °C, Mo KR radiation,
λ ) 0.710 69 Å, µ ) 0.1217 mm-1. The structure, with two symmetry-
independent molecules, was solved by direct methods and refined on
F by full-matrix least-squares methods to give R ) 0.0384, wR )
0.0335, and S ) 1.477 using 556 refined parameters and 5113 observed
reflections with I > 2σ(I) from the 6094 collected with 5° < 2θ < 55°.
For compound 24c: C25H40N2O4Si, Mr ) 460.68, orthorhombic, space
group P212121, a ) 12.532(2), b ) 33.796(2), and c ) 6.389(4) Å, V )
2706(1) Å-3, Z ) 4, Dc ) 1.131 g cm-3, T ) 10 °C, Mo KR radiation, λ
) 0.710 69 Å, µ ) 0.1169 mm-1. The structure was solved by direct
methods and refined on F by full-matrix least-squares methods to give
R ) 0.0427, wR ) 0.0368, and S ) 1.530 using 341 refined parameters
and 3298 observed reflections with I > 3σ(I) from the 10 662 collected
with 5° < 2θ < 60°. For each structure, the enantiomorph was fixed
by the known R configuration of the (silyloxy)ethyl group. The atomic
coordinates have been deposited at the Cambridge Crystallographic
Data Centre.27
Rea ction of Ch ir a l Am in ok eten es w ith Ch ir a l
Im in es Der ived fr om Ch ir a l r-Oxy Ald eh yd es a n d
Ch ir al Am in es. Th e 1,3,4-Match ed an d 1,4-Match ed-
(22) Crystal data for compound 32: C29H41N3O3Si, Mr ) 507.74,
orthorhombic, space group P212121, a ) 11.879(4), b ) 26.427(7), and
c ) 9.052(4) Å, V ) 2842(2) Å-3, Z ) 4, Dc ) 1.187 g cm-3, T ) -100
°C, Mo KR radiation, λ ) 0.710 69 Å, µ ) 0.1161 mm-1. The structure
was solved by direct methods and refined on F by full-matrix least-
squares methods to give R ) 0.0428, wR ) 0.0375, and S ) 1.501 using
325 refined parameters and 3315 observed reflections with I > 2σ(I)
from the 4324 collected with 5° < 2θ < 55°. The enantiomorph was
fixed by the known R configuration of the (silyloxy)ethyl group. The
atomic coordinates have been deposited at the Cambridge Crystal-
lographic Data Centre.27
(23) In this instance, the enamide I was also isolated.
(20) For some examples, see: (a) Cardillo, G.; D’Amico, A.; Orena,
M.; Sandri, S. J . Org. Chem. 1988, 53, 2354. (b) Cardillo, G.; Simone,
A.; Gentilucci, L.; Sabatino, P.; Tomasini, C. Tetrahedron Lett. 1994,
35, 5051. (c) Drewes, S. E.; Malissar, D. G. S.; Roos, G. H. P.
Tetrahedron: Asymmetry 1992, 3, 515. (d) Drewes, S. E.; Malissar, D.
G. S.; Roos, G. H. P. Chem. Ber. 1991, 124, 2913.
(21) Orena, M.; Porzi, G.; Sandri, S. J . Chem. Res., Synop. 1992,
42.

9190 J . Org. Chem., Vol. 61, No. 26, 1996
Palomo et al.
Sch em e 8a
Sch em e 11a
a
Reagents and conditions: (a) 2a , NEt3, CH2Cl2, -78 °C f rt,
20 h, 57%.
Sch em e 9a
a
Reagents and conditions: (a) 2a , NEt3, CH2Cl2, -78 °C f rt,
20 h.
Sch em e 12
reaction, the matched relationship between the amine
component of the imine 44 and the ketene partner affords
an Evans-selective reaction. Thus, under these condi-
tions, a mixture of the Evans adduct 45 and the anti-
Evans adduct 46 was obtained in a ratio of 85:15,
respectively. Both compounds were then separated by
low-pressure column chromatography, and the major
isomer was subjected to the conditions depicted in
Scheme 12. The resulting â-lactam 47, which was N-Boc
protected as 48, was identical to that obtained from the
â-lactam 23a .25
a
Reagents and conditions: (a) 2a , NEt3, CH2Cl2, -78 °C f rt,
20 h.
Sch em e 10
The above results indicate that the concept of double
asymmetric induction can be applied to [2 + 2] cycload-
ditions of ketenes with imines with, in some instances,
reasonable success. However, to facilitate a more ver-
satile entry to â-lactams with stereochemistry dictated
by the ketene partner, we examined alternative ap-
proaches to the required products. Since in the cyclo-
addition reaction of the Evans-Sjo¨gren ketene with R-oxy
aldehyde derived imines 4 and 5 in a 3,4-matched
relationship only one â-lactam product was always
formed (see Scheme 3), we expected that reduction of the
corresponding 4-acyl â-lactams 17 and 18 would be highly
stereoselective owing to the steric bulk of the substituent
at the C3 position. To confirm this, we first subjected
the 4-acetyl â-lactam 17a to treatment with NaBH4, but
unfortunately, no selectivity was observed. In fact, Miller
and co-workers26 also showed the same lack of stereose-
lectivity in the reduction of closely related 4-acetyl
â-lactams. However, the reduction of 17a carried out by
means of L-Selectride proceeded to give the desired
carbinol 51 as virtually a single diastereomer. Likewise,
18a furnished 52 without detectable amounts of the
corresponding epimeric carbinol. In view of these results,
we also considered another way to obtain the correspond-
3,4-m ism a tch ed Ca ses. In addition to this double
asymmetric induction we also sought information about
the behavior of a third chiral component on these
reactions. For this purpose, we elected to use imines
derived from lactaldehyde and 1-phenylethylamine for
which both enantiomers are commercially available and
cheap. According to the known induction sense of this
amine in â-lactam synthesis,24 we first checked the fully
matched reaction between the Evans-Sjo¨gren acid chlo-
ride 2a and the imine 37 (Scheme 8). By this means,
the â-lactam 38 was obtained as the single reaction
product. Next, the partially matched case shown in
Scheme 9 was examined. Thus, in this experiment, the
sense of asymmetric induction establishes a matched
relationship between the R-oxy aldehyde and the amine
component of the imine partner and a mismatched
relationship with respect to the ketene partner. As a
result, a mixture of â-lactams 40/41 was obtained in a
30:70 ratio, thus indicating that the additional stereo-
genic center of the amine component slightly reinforces
the sense of asymmetric induction exerted by the alde-
hyde component. The major anti-Evans adduct 41 was
separated by crystallization from ethanol and the minor
â-lactam 40 by preparative HPLC. Correlation of the
stereochemical course of these reactions was established
by conversion of both 41 and 24a (Scheme 10) into the
â-lactam 42 which was isolated as the N-Boc derivative
43. The most interesting stereochemical variant is,
however, the reaction depicted in Scheme 11, in this
(25) For an enolate-imine condensation route to these â-lactams
with relative trans stereochemistry at the C3-C4 positions, see:
Cainelli, G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta, G.
Tetrahedron 1996, 52, 1685.
(26) Farouz, F.; Miller, M. J . Tetrahedron Lett. 1991, 32, 3305.
(27) The author has deposited atomic coordinates for these struc-
tures with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
(24) (a) Ojima, I.; Suga, S.; Abe, R. Chem. Lett. 1980, 853. (b) Alcaide,
B.; Dominguez, G.; Escobar, G.; Parreno, M.; Plumet, J . Heterocycles
1986, 24, 1579. (c) Thomas, R. C. Tetrahedron Lett. 1989, 46, 1579.

Asymmetric Synthesis of â-Lactams
J . Org. Chem., Vol. 61, No. 26, 1996 9191
Sch em e 13a
extracted with methylene chloride (3 × 100 mL). The organic
extracts were combined and dried over MgSO4. Concentration
in vacuo afforded the desired compound 9b or 9c, which was
utilized in the next step without further purification.
Gen er a l P r oced u r e B. Methyl bromoacetate (4.68 mL,
50 mmol) was added dropwise at 0 °C under a nitrogen
atmosphere to a suspension of the imidazolidinone 29 (9.6 g,
50 mmol) and sodium hydride (1.2 g, 50 mmol) in dry THF
(75 mL). The resulting mixture was allowed to stir at 0 °C
for 2 h. Then, a solution of NaOH in water/THF (10 g, 100
mL of water, 125 mL of THF) was added, and the mixture
was allowed to stir at room temperature for 2 h. Finally the
mixture was acidified with concd HCl and extracted with
methylene chloride (3 × 100 mL). The organic extracts were
combined and dried over MgSO4. Concentration in vacuo
afforded the desired compound 30, which was utilized in the
next step without further purification.
[(4S)-2-Oxo-4-isopr opyloxazolidin -3-yl]acetic Acid (9b).
The title compound was prepared from 4(S)-isopropyloxazoli-
din-2-one (8b) following general procedure A; yield 95%. An
analytical sample was purified by column chromatography
(70-230 mesh, methylene chloride as eluant): white low-
a
Reagents and conditions: (a) p-TosOH, THF, H2O; (b) NaIO4,
KMnO4, Me2CO, H2O, rt, 6 h; (c) Cl2SO, CH2Cl2, reflux, 3 h, then
R1MgX (1.3 equiv), THF, -40 °C f rt; (d) L-Selectride, THF, -60
°C, 1 h.
melting solid. [R]25 ) +62.6° (c ) 1.0, CH2Cl2); IR (NaCl): υ
D
3620-2520 cm-1 (OH); 1740 cm-1 (CdO); 1735 (CdO); 1H
NMR (CDCl3, δ ppm): 8.92 (sb, 1H); 4.34 (dd, 1H, J ) 8.7 Hz,
J ) 6.3 Hz); 4.31 (d, 1H, J ) 18.0 Hz); 4.10 (t, 1H, J ) 6.3
Hz); 4.03-3.97 (m, 1H); 3.67 (d, 1H, J ) 18.0 Hz); 2.04-1.92
ing 4-acyl â-lactams that would be more general in scope.
As Scheme 13 illustrates, the 4-carboxy â-lactam 50,
easily available from the â-lactam 49, fulfills this crite-
rion. For example, the coupling reaction of the acid
chloride derived from 50 with both methylmagnesium
bromide and phenylmagnesium bromide as representa-
tive Grignard reagents provided the ketones 17a and 18a
in 75% and 70% yields, respectively, and, most satisfac-
torily, without overaddition products. Therefore, both
approaches developed here, the cycloaddition reaction
and the diastereoselective reduction of 4-acyl â-lactams,
are complementary and open a way to the synthesis of
1(R)- and 1(S)-hydroxyalkyl â-lactams with the same cis
stereochemistry between the C3 and C4 positions.
(m, 1H); 0.89 (d, 1H, J ) 6.1 Hz); 0.85 (d, 1H, J ) 6.2 Hz). 13
C
NMR (CDCl3, δ ppm): 171.1, 159.5, 63.8, 59.4, 43.3, 27.4, 17.5,
14.5. Anal. Calcd for C8H13NO4 (187.19): C, 51.33; H, 6.99;
N, 7.48. Found: C, 50.99; H, 7.01; N, 7.39.
[(4S)-4-ter t-Bu tyl-2-oxooxa zolid in -3-yl]a cetic Acid (9c).
The title compound was prepared from (4S)-4-tert-buthyl-
oxazolidin-2-one (8c) following general procedure A: yield 91%;
white solid recrystallized from methylene chloride/hexane; mp
162-164 °C (CH2Cl2, hexane). [R]25 ) +34.4° (c ) 1.0, CH2-
D
Cl2). IR (KBr): υ 3550-2400 cm-1 (OH); 1747 cm-1 (CdO);
1736 (CdO). 1H NMR (CDCl3, δ ppm): 8.91-8.72 (sb, 1H);
4.52 (d, 1H, J ) 18.4 Hz); 4.42 (t, 1H, J ) 9.0 Hz); 4.22 (dd,
1H, J ) 4.7 Hz, J ) 9.0 Hz); 3.95 (d, 1H, J ) 18.4 Hz); 3.74
(dd, 1H, J ) 4.7 Hz, J ) 9.0 Hz); 0.98 (s, 9H). 13C NMR
(CDCl3, δ ppm): 172.9, 160.6, 65.5, 64.2, 46.8, 34.5, 25.5. Anal.
Calcd for C9H15NO4 (201.22): C, 53.72; H, 7.51; N, 6.96.
Found: C, 53.68; H, 7.32; N, 7.09.
Exp er im en ta l Section
[(4R,5S)-1,5-Dim eth yl-2-oxo-4-ph en ylim idazolidin -3-yl]-
a cetic Acid (30). The title compound was prepared from
(4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one (29) following
general procedure B: yield 92%; white solid recrystallized from
Melting points were determined on a capillary apparatus
and are uncorrected. Proton nuclear magnetic resonance (300
MHz) spectra and 13C NMR 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
ethyl acetate/hexane; mp 168-170 °C (AcOEt, hexane). [R]25
D
) -34.0° (c ) 1.0, MeOH). IR (KBr): υ 2892-2858 cm-1 (OH);
1760 cm-1 (CdO); 1748 (CdO). 1H NMR (CDCl3, δ ppm):
7.38-7.14 (m, 5H); 6.94-6.62 (sb, 1H); 4.94 (d, 1H, J ) 9.1
Hz); 4.35 (d, 1H, J ) 18.1 Hz); 3.95-3.86 (m, 1H); 3.37 (d, 1H,
J ) 18.1 Hz); 2.81 (s, 3H); 0.74 (d, 3H, J ) 6.6 Hz). 13C NMR
(CDCl3, δ ppm): 172.5, 161.6, 134.9, 128.7, 128.4, 128.0, 62.3,
55.8, 43.7, 28.7, 14.5. Anal. Calcd for C13H16N2O3 (248.28):
C, 62.89; H, 6.49; N, 11.28. Found: C, 62.57; H, 6.31; N, 11.04.
Gen er a l P r oced u r e for â-La cta m F or m a tion . Triethyl-
amine (6.36 mL, 45 mmol) was added at -78 °C to a solution
of the corresponding acyl choride 1, 2a , 2b, 2c, or 31 (30 mmol)
in dry methylene chloride (90 mL). After 15 min, a solution
of the corresponding imine (33 mmol) in dry toluene was added
dropwise at the same temperature and the resulting mixture
was stirred under nitrogen atmosphere at 0 °C for 2 h and at
room temperature overnight. Then, the reaction mixture was
successively washed with water (100 mL), 0.1 N HCl (100 mL),
and a saturated solution of NaHCO3 (100 mL). The organic
layer was dried over MgSO4 and filtered, and the solvent was
evaporated under reduced pressure to give the corresponding
crude â-lactam, which was further purified by column chro-
matography and then by preparative HPLC when necessary.
cis-(3R,4R)-1-Ben zyl-4-[(4S)-2,2-d im eth yl-1,3-d ioxola n -
4-yl]-3-[(4R)-2-oxo-4-p h en yloxa zolid in -3-yl]a zet id in -2-
on e (10). The title compound was prepared from the acid
chloride 1 and the imine 3 following the general procedure.
The crude â-lactam was purified by colum chromatography
(silica gel 70-230 mesh, methylene chloride/hexane 1:2 as
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 using a UV detector (254 nm). Flash chromatography was
executed with Merck kiesegel 60 (230-400 mesh) using
mixtures of ethyl acetate and hexane as eluants. Acetonitrile
and hexane were dried and purified by distillation. Tetra-
hydrofuran was distilled over sodium and benzophenone
(indicator). Methylene chloride was shaken with concentrated
sulfuric acid, dried over potassium carbonate, and distilled.
Commercially available compounds were used without further
purification. Compound 9a was prepared according to a
literature procedure.6d
Gen er a l P r oced u r e for th e P r ep a r a tion of Ca r boxylic
Acid s 9b, 9c, a n d 30. Gen er a l P r oced u r e A. Methyl
bromoacetate (4.68 mL, 50 mmol) was added dropwise at 0 °C
under a nitrogen atmosphere to a suspension of the corre-
sponding oxazolidinone (50 mmol) and sodium hydride (1.2 g,
50 mmol) in dry THF (75 mL). The resulting mixture was
allowed to stir at 0 °C for 2 h. Then, a solution of NaOH in
water/THF (10 g, 100 mL of water, 125 mL of THF) was added,
and the mixture was allowed to stir at room temperature for
2 h. Finally the mixture was acidified with concd HCl and

9192 J . Org. Chem., Vol. 61, No. 26, 1996
Palomo et al.
eluant): white solid recrystallized from ethanol; yield 57%; mp
2H); 5.30 (d, 1H, J ) 8.8 Hz); 4.93 (d, 1H, J ) 15.2 Hz); 4.39
(d, 1H, J ) 15.2 Hz); 4.15 (t, 1H, J ) 8.6 Hz); 4.04 (dd, 1H, J
) 5.2 Hz, J ) 8.8 Hz); 3.85 (t, 1H, J ) 8.6 Hz); 3.70 (d, 1H, J
) 5.2 Hz); 2.71-2.62 (m, 1H); 0.78 (s, 9H); 0.00 (s, 3H); -0.30
(s, 3H). 13C NMR (CDCl3, δ ppm): 164.9, 156.9, 141.0, 136.3,
129.4, 129.2, 128.8, 128.6, 128.1, 127.7, 127.6, 127.4, 127.0,
75.9, 70.4, 63.7, 59.8, 58.5, 45.6, 25.8, 17.9, -4.4, -4.5. Anal.
Calcd for C32H38N2O4Si (542.75): C, 70.81; H, 7.06; N, 5.16.
Found: C, 70.69; H, 6.95; N, 5.03.
176-178 °C (ethanol). [R]25 ) -88.6° (c ) 1.0, CH2Cl2). IR
D
(KBr): υ 1751 cm-1 (CdO); 1741 cm-1 (CO). 1H NMR (DMSO-
d6 at 90 °C, δ ppm): 7.46-7.19 (m, 10H); 4.99 (dd, 1H, J )
5.0 Hz, J ) 8.9 Hz); 4.74 (t, 1H, J ) 8.9 Hz); 4.50-4.44 (m,
2H); 4.23-4.15 (m, 2H); 4.05-3.97 (m, 2H); 3.66-3.60 (m, 2H);
1.23 (s, 3H); 1.17 (s, 3H). 13C NMR (DMSO-d6 at 90 °C, δ
ppm): 163.3, 156.9, 138.6, 136.1, 128.9, 128.6, 128.1, 127.8,
127.1, 126.9, 108.6, 75.5, 70.2, 65.6, 61.0, 59.8, 59.1, 45.1, 26.3,
24.9. Anal. Calcd for C24H26N2O5 (422.48): C, 68.23; H, 6.20;
N, 6.63. Found: C, 68.07; H, 6.12; N, 6.43.
cis-(3S,4S)-1-Ben zyl-4-[(4S)-2,2-d im eth yl-1,3-d ioxola n -
4-yl]-3-[(4S)-2-oxo-4-p h en yloxa zolid in -3-yl]a zet id in -2-
on e (19). The title compound was prepared from the acid
chloride 2a and the imine 3 following the general procedure.
The crude â-lactam was purified by column chromatography
(silica gel 70-230 mesh, methylene chloride/hexane 1:2 as
eluant) and the title compound was separated from the anti-
Evans isomer by preparative HPLC (ethyl acetate as eluant,
10 mL/min, tR ) 10.05 min): white solid recrystallized from
ethanol; yield 26%; mp 166-168 °C (ethanol). [R]25D ) +100.2°
(c ) 1.0, CH2Cl2). IR (NaCl): υ 1754 cm-1 (CdO); 1750 cm-1
(CO). 1H NMR (CDCl3, δ ppm): 7.45-7.22 (m, 10H); 4.99 (t,
1H, J ) 8.6 Hz); 4.65 (t, 1H, J ) 8.6 Hz); 4.46 (d, 1H, J ) 15.6
Hz); 4.32 (d, 1H, J ) 15.6 Hz); 4.32 (m, 1H): 4.19 (d, 1H, J )
5.1 Hz); 4.17 (t, 1H, J ) 8.6 Hz); 3.53-3.46 (m, 2H); 3.36 (dd,
1H, J ) 5.1 Hz, J ) 8.6 Hz); 1.39 (s, 3H); 1.28 (s, 3H). 13C
NMR (CDCl3, δ ppm): 164.5, 157.5, 136.5, 135.2, 129.3, 128.8,
128.0, 127.8, 127.6, 127.3, 109.0, 74.0, 70.5, 67.7, 61.4, 60.6,
60.4, 45.3, 26.7, 25.0. Anal. Calcd for C24H26N2O5 (422.48):
C, 68.23; H, 6.20; N, 6.63. Found: C, 68.10; H, 6.13; N, 6.37.
cis-(3S,4S)-1-Ben zyl-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]eth yl]-3-[(4S)-2-oxo-4-ph en yloxazolidin -3-yl]azetidin -
2-on e (23a ). The title compound was prepared from the acid
chloride 2a and the imine 6 following the general procedure
and separated from the anti-Evans isomer by flash column
chromatography (silica gel 230-400 mesh, methylene chloride/
hexane 1:2 as eluant): syrup purified by preparative HPLC
(ethyl acetate as eluant, 10 mL/min, tR ) 9.80 min); yield 21%.
cis-(3S,4S)-1-Ben zyl-4-[(1S)-[(ter t-bu tyld im eth ylsilyl)-
oxy]eth yl]-3-[(4S)-2-oxo-4-ph en yloxazolidin -3-yl]azetidin -
2-on e (13a ). The title compound was prepared from the acid
chloride 2a and the imine 4 following the general procedure.
The crude â-lactam was purified by column chromatography
(silica gel 70-230 mesh, methylene chloride/hexane 1:2 as
eluant): white solid recrystallized from ethanol; yield 56%; mp
172-174 °C (ethanol). [R]25 ) +125.4° (c ) 1.0, CH2Cl2). IR
D
(KBr): υ 1751 cm-1 (CdO); 1748 cm-1 (CO). 1H NMR (DMSO-
d6 at 90 °C, δ ppm): 7.45-7.15 (m, 10H); 5.00 (dd, 1H, J )
5.0 Hz, J ) 8.9 Hz); 4.72 (t, 1H, J ) 15.4 Hz); 4.42 (d, 1H, J
) 5.3 Hz); 4.18 (d, 1H, J ) 15.4 Hz); 4.15 (dd, 1H, J ) 5.0 Hz,
J ) 8.9 Hz); 4.02-3.93 (m, 1H); 3.49 (dd, 1H, J ) 5.3 Hz, J )
9.0 Hz); 1.09 (d, 3H, J ) 6.1 Hz); 0.85 (s, 9H); 0.04 (s, 3H);
-0.20 (s, 3H). 13C NMR (DMSO-d6 at 90 °C, δ ppm): 164.1,
156.9, 138.5, 135.9, 128.8, 128.5, 128.1, 127.1, 126.9, 126.8,
69.9, 68.8, 62.7, 59.7, 59.1, 45.1, 25.5, 20.3, 17.2, -4.5, -4.7.
Anal. Calcd for C27H36N2O4Si (480.68): C, 67.47; H, 7.55; N,
5.83. Found: C, 67.39; H, 7.38; N, 5.92.
cis-(3S,4S)-1-Ben zyl-4-[(1S)-[(ter t-bu tyld im eth ylsilyl)-
oxy]eth yl]-3-[(4S)-2-oxo-4-isop r op yloxa zolid in -3-yl]a ze-
tid in -2-on e (13b). The title compound was prepared from
the acid chloride 2b and the imine 4 following the general
procedure. The crude â-lactam was purified by flash column
chromatography (silica gel 230-240 mesh, ethyl acetate/
hexane 1:3 as eluant): white solid recrystallized from ethanol;
yield 58%; mp 233-234 °C (ethanol). [R]25D ) +97.0° (c ) 1.0,
CH2Cl2). IR (KBr): υ 1764 cm-1 (CdO); 1737 cm-1 (CO). 1H
NMR (CDCl3, δ ppm): 7.36-7.22 (m, 5H); 4.89 (d, 1H, J )
14.7 Hz); 4.43-4.11 (m, 4H); 4.22 (d, 1H, J ) 14.7 Hz); 3.91-
3.71 (m, 1H); 3.47 (dd, 1H, J ) 5.1 Hz, J ) 9.3 Hz); 2.08-2.00
(m, 1H); 1.04 (d, 3 Hz, J ) 5.9 Hz); 1.01 (d, 3H, J ) 6.8 Hz);
0.94 (s, 9H); 0.92 (d, 3H, J ) 7.1 Hz); 0.14 (s, 3H); 0.13 (s,
3H). 13C NMR (CDCl3, δ ppm): 164.8, 157.9, 135.9, 128.7,
128.4, 127.6, 69.2, 63.1, 62.2, 59.8, 59.6, 45.9, 28.6, 25.9, 20.9,
17.9, 13.7, -4.2, -4.4. Anal. Calcd for C24H38N2O4Si
(446.66): C, 64.54; H, 8.57; N, 6.27. Found: C, 64.39; H, 8.45;
N, 6.15.
cis-(3S,4S)-1-Ben zyl-4-[(1S)-[(ter t-bu tyld im eth ylsilyl)-
oxy]eth yl]-3-[(4S)-4-ter t-bu tyl-2-oxooxa zolid in -3-yl]a ze-
tid in -2-on e (13c). The title compound was prepared from the
acid chloride 2c and the imine 4 following the general
procedure. The crude â-lactam was purified by flash column
chromatography (silica gel 230-240 mesh, ethyl acetate/
hexane 1:4 as eluant): white solid recrystallized from ethanol;
yield 83%; mp 198-200 °C (ethanol). [R]25D ) +47.3° (c ) 1.0,
CH2Cl2). IR (KBr): υ 1762 cm-1 (CdO); 1734 cm-1 (CO). 1H
NMR (CDCl3, δ ppm): 7.41-7.26 (m, 5H); 4.87 (d, 1H, J )
14.8 Hz); 4.52-4.32 (m, 2H); 4.28-4.21 (m, 1H); 4.27 (d, 1H,
J ) 5.2 Hz); 4.24 (d, 1H, J ) 14.8 Hz); 3.52 (dd, 1H, J ) 5.2
Hz, J ) 9.2 Hz); 3.34-3.20 (sb, 1H); 1.07 (d, 3H, J ) 6.1 Hz);
1.02 (s, 9H); 0.93 (s, 9H); 0.12 (s, 6H). 13C NMR (CDCl3, δ
ppm): 165.5, 157.3, 136.2, 128.7, 128.6, 127.5, 66.1, 65.3, 63.9,
61.7, 45.8, 35.8, 25.9, 25.7, 20.9, 17.8, -4.2, -4.3. Anal. Calcd
for C25H40N2O4Si (460.69): C, 65.18; H, 8.75; N, 6.08. Found:
C, 64.90; H, 8.57; N, 5.99.
[R]25 ) +73.61° (c ) 1.0, CH2Cl2). IR (NaCl): υ 1757 cm-1
D
(CdO); 1752 cm-1 (CO). 1H NMR (CDCl3, δ ppm): 7.49-7.17
(m, 10H); 4.91 (dd, 1H, J ) 7.5 Hz, J ) 9.0 Hz); 4.78 (d, 1H,
J ) 15.2 Hz); 4.66 (t, 1H, J ) 9.0 Hz); 4.32-4.27 (m, 1H0;
4.18 (dd, 1H, J ) 7.5 Hz, J ) 9.0 Hz); 4.13 (d, 1H, J ) 5.1 Hz);
3.33 (dd, 1H, J ) 5.1 Hz, J ) 8.3 Hz); 3.33 (dd, 1H, J ) 5.1
Hz, J ) 8.3 Hz); 1.16 (d, 3H, J ) 6.2 Hz); 0.90 (s, 9H); 0.11 (s,
3H); 0.10 (s, 3H). 13C NMR (CDCl3, δ ppm): 165.8, 157.5,
137.3, 135.4, 129.6, 129.4, 128.8, 128.1, 127.6, 127.4, 70.5, 67.6,
64.4, 60.7, 60.2, 46.0, 26.0, 22.3, 18.1, -3.0, -3.7.
cis-(3S,4S)-1-Ben zyl-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]eth yl]-3-[(4S)-2-oxo-4-isop r op yloxa zolid in -3-yl]a ze-
tid in -2-on e (23b). The title compound was prepared from
the acid chloride 2b and the imine 6 following the general
procedure and separated from the anti-Evans isomer by flash
column chromatography (silica gel 230-400 mesh, ethyl
acetate/hexane 1:4 as eluant): white solid recrystallized from
ethanol; yield 39%; mp 110-112 °C (ethanol). [R]25D ) +25.7°
(c ) 1.0, CH2Cl2). IR (KBr): υ 1751 cm-1 (CdO); 1749 cm-1
(CO). 1H NMR (CDCl3, δ ppm): 7.37-7.25 (m, 5H); 4.83 (d,
1H, J ) 15.4 Hz); 4.34-4.31 (m, 1H); 4.33 (d, 1H, J ) 5.3 Hz);
4.26 (t, 1H, J ) 9.0 Hz); 4.16 (dd, 1H, J ) 5.0 Hz, J ) 9.0 Hz);
4.14 (d, 1H, J ) 15.4 Hz); 3.78 (ddd, 1H, J ) 3.5 Hz, J ) 5.0
Hz, J ) 9.0 Hz); 3.44 (dd, 1H, J ) 5.3 Hz, J ) 8.1 Hz); 2.18-
2.08 (m, 1H); 1.21 (d, 3H, J ) 6.2 Hz); 1.02 (d, 3H, J ) 6.8
Hz); 0.89 (d, 3H, J ) 6.9 Hz); 0.84 (s, 9H); 0.05 (s, 3H). 13C
NMR (CDCl3, δ ppm): 166.2, 157.8, 135.5, 128.8, 128.1, 127.6,
67.2, 64.2, 63.0, 60.1, 59.8, 46.1, 27.6, 25.8, 22.2, 17.9, 17.5,
13.4, -3.2, -4.1. Anal. Calcd for C24H38N2O4Si (446.66): C,
64.54; H, 8.57; N, 6.27. Found: C, 64.31; H, 8.35; N, 6.04.
cis-(3R,4R)-1-Ben zyl-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]eth yl]-3-[(4S)-2-oxo-4-ph en yloxazolidin -3-yl]azetidin -
2-on e (24a ). The title compound was prepared from the acid
chloride 2a and the imine 6 following the general procedure
and separated from the Evans isomer by column chromatog-
raphy (silica gel 70-230 mesh, methylene chloride/hexane 1:2
as eluant): white solid recrystallized from ethanol; yield 31%;
cis-(3S,4S)-1-Ben zyl-4-[(1S)-[(ter t-bu tyld im eth ylsilyl)-
oxy]ben zyl]-3-[(4S)-2-oxo-4-p h en yloxa zolid in -3-yl]a zeti-
d in -2-on e (14a ). The title compound was prepared from the
acid chloride 2a and the imine 5 following the general
procedure. The crude â-lactam was purified by flash column
chromatography (silica gel 230-240 mesh, ethyl acetate/
hexane 1:2 as eluant): white solid recrystallized from ethanol;
yield 65%; mp 175-177 °C (ethanol). [R]25 ) +176.7° (c )
mp 148-150 °C (ethanol). [R]25 ) +21.4° (c ) 1.0, CH2Cl2).
D
D
1.0, CH2Cl2). IR (KBr): υ 1762 cm-1 (CdO); 1744 cm-1 (CO).
IR (KBr): υ 1761 cm-1 (CdO); 1753 cm-1 (CO). 1H NMR
(CDCl3, δ ppm): 7.40-7.21 (m, 10H); 4.88 (t, 1H, J ) 8.6 Hz);
1H NMR (CDCl3, δ ppm): 7.51-7.16 (m, 13H); 7.01-6.98 (m,

Asymmetric Synthesis of â-Lactams
J . Org. Chem., Vol. 61, No. 26, 1996 9193
4.81 (d, 1H, J ) 14.8 Hz); 4.65 (t, 1H, J ) 8.6 Hz); 4.52-4.47
(m, 1H); 4.32-4.26 (m, 2H); 4.18 (d, 1H, J ) 14.8 Hz); 3.30
(dd, 1H, J ) 5.6 Hz, J ) 8.8 Hz); 0.96 (d, 3H, J ) 6.1 Hz); 0.93
(s, 9H); 0.16 (s, 3H); 0.15 (s, 3H). 13C NMR (CDCl3, δ ppm):
165.0, 157.9, 136.2, 135.9, 129.7, 129.2, 128.6, 128.5, 127.9,
127.6, 69.9, 68.1, 63.2, 62.3, 60.7, 45.8, 26.0, 21.5, 17.9, -4.1,
-4.3. Anal. Calcd for C27H36N2O4Si (480.68): C, 67.47; H,
7.55; N, 5.83. Found: C, 67.20; H, 7.45; N, 5.43.
8.7 Hz); 4.16 (dd, 1H, J ) 5.4 Hz, J ) 8.8 Hz); 3.86 (t, 1H, J
) 8.7 Hz); 3.62-3.55 (m, 1H); 1.58-1.34 (m, 1H); 0.76 (s, 9H);
0.52 (d, 3H, J ) 6.7 Hz); 0.37 (d, 3H, J ) 6.4 Hz); -0.06 (s,
3H); -0.30 (s, 3H). 13C NMR (DMSO-d6 at 90 °C, δ ppm):
165.3, 157.3, 140.2, 135.9, 128.0, 127.9, 127.2, 127.0, 126.7,
75.4, 64.2, 62.7, 62.0, 61.0, 45.1, 28.8, 25.3, 17.8, 14.8, -4.9,
-5.1. Anal. Calcd for C29H40N2O4Si (508.73): C, 68.47 H, 7.92;
N, 5.51. Found: C, 68.31; H, 7.85; N, 5.47.
cis-(3R,4R)-1-Ben zyl-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]eth yl]-3-[(4S)-2-oxo-4-isop r op yloxa zolid in -3-yl]a ze-
tid in -2-on e (24b). The title compound was prepared from
the acid chloride 2b and the imine 6 following the general
procedure and separated from the Evans isomer by flash
column chromatography (silica gel 230-400 mesh, ethyl
acetate/hexane 1:4 as eluant): white solid recrystallized from
ethanol; yield 13%; mp 115-117 °C (ethanol). [R]25D ) -48.7°
(c ) 1.0, CH2Cl2). IR (KBr): υ 1750 cm-1 (CdO); 1747 cm-1
(CO). 1H NMR (CDCl3, δ ppm): 7.37-7.24 (m, 5H); 4.89 (d,
1H, J ) 14.7 Hz); 4.81 (d, 1H, J ) 5.1 Hz); 4.25 (t, 1H, J ) 8.7
Hz); 4.21-4.14 (m, 3H); 3.81-3.75 (m, 1H); 3.51 (dd, 1H, J )
5.1 Hz, J ) 8.1 Hz); 2.55-2.42 (m, 1H); 1.11 (d, 3H, J ) 6.1
Hz); 0.94 (s, 9H); 0.91 (d, 3H, J ) 6.8 Hz); 0.90 (d, 3H, J ) 7.0
Hz); 0.14 (s, 3H); 0.13 (s, 3H). 13C NMR (CDCl3, δ ppm): 165.3,
157.9, 135.4, 128.8, 128.3, 127.8, 69.2, 63.5, 62.3, 62.1, 60.7,
46.0, 28.7, 25.9, 21.6, 18.5, 18.0, 14.5, -4.1, -4.2. Anal. Calcd
for C24H38N2O4Si (446.66): C, 64.54; H, 8.57; N, 6.27. Found:
C, 64.28; H, 8.43; N, 6.12.
cis-(3R,4R)-1-Ben zyl-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]ben zyl]-3-[(4S)-2-oxo-4-p h en yloxa zolid in -3-yl]a zeti-
d in -2-on e (26a ). The title compound was prepared from the
acid chloride 2a and the imine 7 following the general
procedure and was separated from the Evans isomer by flash
column chromatography (silica gel 230-400 mesh, ethyl
acetate/hexane 1:2 as eluant): white solid recrystallized from
ethanol; yield 47%; mp 189-191 °C (ethanol). [R]25D ) -24.3°
(c ) 1.0, CH2Cl2). IR (KBr): υ 1765 cm-1 (CdO); 1746 cm-1
(CO). 1H NMR (CDCl3, δ ppm): 7.52-7.22 (m, 11H); 7.09-
7.04 (m, 2H); 6.18-6.15 (d, 2H); 5.75 (d, 1H, J ) 9.0 Hz); 4.99
(d, 1H, J ) 14.9 Hz); 4.86 (dd, 1H, J ) 8.3 Hz, J ) 11.1 Hz);
4.50 (d, 1H, J ) 14.9 Hz); 4.48 (t, 1H, J ) 8.3 Hz); 3.97 (dd,
1H, J ) 5.7 Hz, J ) 9.0 Hz); 3.82 (d, 1H, J ) 5.7 Hz); 3.77 (dd,
1H, J ) 8.3 Hz, J ) 11.1 Hz); 0.87 (s, 9H); 0.07 (s, 3H); -0.20
(s, 3H). 13C NMR (CDCl3, δ ppm): 166.2, 158.3, 141.4, 136.1,
134.1, 130.0, 129.7, 129.6, 129.2, 129.1, 127.4, 127.3, 75.8, 70.2,
64.2, 62.8, 59.8, 45.5, 25.9, 17.9, -4.4, -4.5. Anal. Calcd for
C32H38N2O4Si (542.75): C, 70.81; H, 7.06; N, 5.16. Found: C,
71.03; H, 7.34; N, 5.56.
cis-(3R,4R)-1-Ben zyl-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]eth yl]-3-[(4S)-4-ter t-bu tyl-2-oxooxa zolid in -3-yl]a ze-
tid in -2-on e (24c). The title compound was prepared from the
acid chloride 2c and the imine 6 following the general
procedure. The crude â-lactam was purified by flash column
chromatography (silica gel 230-400 mesh, ethyl acetate/
hexane 1:4 as eluant): white solid recrystallized from ethanol;
yield 80%. [R]25D ) -31.6° (c ) 1.0, CH2Cl2). IR (KBr): υ 1766
cm-1 (CdO); 1739 cm-1 (CO). 1H NMR (CDCl3, δ ppm): 7.34-
7.26 (m, 5H); 4.88 (d, 1H, J ) 14.9 Hz); 4.83 (m, 1H); 4.45 (d,
1H, J ) 9.3 Hz); 4.30 (d, 1H, J ) 14.9 Hz); 4.21 (d, 1H, J )
5.2 Hz); 4.19 (dd, 1H, J ) 5.1 Hz, J ) 9.3 Hz); 3.53 (dd, 1H, J
) 5.2 Hz, J ) 9.3 Hz); 3.48 (dd, 1H, J ) 5.1 Hz, J ) 9.3 Hz);
1.2 (d, 3H, J ) 6.0 Hz); 0.94 (s, 9H); 0.92 (s, 9H); 0.17 (s, 3H);
0.14 (s, 3H). 13C NMR (CDCl3, δ ppm): 165.5, 159.4, 136.1,
128.7, 128.5, 127.5, 68.8, 68.3, 65.5, 65.1, 63.6, 45.6, 34.5, 26.0,
25.2, 22.3, 17.9, -4.1, -4.5. Anal. Calcd for C25H40N2O4Si
(460.69): C, 65.18; H, 8.75; N, 6.08. Found: C, 64.97; H, 8.62;
N, 5.93.
cis-(3R,4R)-1-Ben zyl-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]ben zyl]-3-[(4S)-4-ter t-bu tyl-2-oxooxa zolid in -3-yl]a ze-
tid in -2-on e (26c). The title compound was prepared from the
acid chloride 2c and the imine 7 following the general
procedure. The crude â-lactam was purified by flash column
chromatography (silica gel 230-400 mesh, ethyl acetate/
hexane 1:4 as eluant): white solid recrystallized from ethanol;
yield 82%; mp 228-230 °C (ethanol). [R]25D ) -21.0° (c ) 1.0,
CH2Cl2). IR (KBr): υ 1765 cm-1 (CdO); 1736 cm-1 (CO). 1H
NMR (CDCl3, δ ppm): 7.40-7.23 (m, 10H); 5.79 (d, 1H, J )
9.0 Hz); 4.95 (d, 1H, J ) 14.9 Hz); 4.51 (d, 1H, J ) 14.9 Hz);
4.33 (t, 1H, J ) 9.2 Hz); 4.18 (dd, 1H, J ) 5.5 Hz, J ) 9.0 Hz);
4.12 (d, 1H, J ) 5.5 Hz); 3.99 (dd, 1H, J ) 5.3 Hz, J ) 9.2 Hz);
3.29 (dd, 1H, J ) 5.3 Hz, J ) 9.2 Hz); 0.79 (s, 9H); 0.32 (s,
9H); -0.02 (s, 3H); -0.29 (s, 3H). 13C NMR (CDCl3, δ ppm):
166.3, 159.7, 140.9, 1363, 128.7, 128.5, 128.3, 128.1, 127.5,
76.0, 68.3, 65.1, 63.5, 45.6, 33.5, 25.9, 24.5, 18.0, -4.4. Anal.
Calcd for C30H42N2O4Si (522.76): C, 68.93; H, 8.10; N, 5.36.
Found: C, 69.03; H, 7.84; N, 5.18.
cis-(3R,4R)-1-Ben zyl-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]eth yl]-3-[(4R,5S)-1,5-d im eth yl-2-oxo-4-p h en ylim id a -
zolid in -3-yl]a zetid in -2-on e (32). The title compound was
prepared from the acid chloride 31 and the imine 6 following
the general procedure. The crude â-lactam was purified by
flash column chromatography (silica gel 230-400 mesh, ethyl
acetate/hexane 1:4 as eluant): white solid recrystallized from
ethanol; yield 85%; mp 176-178 °C (ethanol). [R]25D ) -88.8°
(c ) 1.0, CH2Cl2). IR (KBr): υ 1757 cm-1 (CdO); 1697 cm-1
(N-CO-N). 1H NMR (CDCl3, δ ppm): 7.35-7.28 (m, 10H);
4.82 (d, 1H, J ) 8.5 Hz); 4.75 (d, 1H, J ) 15.4 Hz); 4.38-4.28
(m, 1H); 4.33 (d, 1H, J ) 15.4 Hz); 4.33 (d, 1H, J ) 5.2 Hz);
3.95-3.86 (m, 1H); 3.54 (dd, 1H, J ) 5.2 Hz); 2.75 (s, 3H);
1.19 (d, 3H, J ) 6.1 Hz); 0.99 (s, 9H); 0.82 (d, 3H, J ) 6.3 Hz);
0.16 (s, 3H); 0.14 (s, 3H). 13C NMR (CDCl3, δ ppm): 166.3,
161.4, 136.3, 136.1, 128.6, 128.5, 128.2, 127.4, 69.7, 62.8, 62.1,
61.4, 56.8, 45.7, 29.0, 25.9, 20.7, 17.8, 15.1, -4.4, -4.5. Anal.
Calcd for C29H41N3O3Si (507.75): C, 68.60; H, 8.14; N, 8.28.
Found: C, 68.79; H, 8.06; N, 7.74.
cis-(3S,4S)-1-Ben zyl-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]ben zyl]-3-[(4S)-2-oxo-4-p h en yloxa zolid in -3-yl]a zeti-
d in -2-on e (25a ). The title compound was prepared from the
acid chloride 2a and the imine 7 following the general
procedure. The crude â-lactam was purified by flash column
chromatography (silica gel 230-400 mesh, ethyl acetate/
hexane 1:2 as eluant). The title compound was then separated
from the anti-Evans isomer by preparative HPLC (ethyl
acetate/hexane 2:1 as eluant, 10 mL/min, tR ) 12.82 min):
syrup; yield 20%. [R]25 ) +3.59° (c ) 1.0, CH2Cl2). IR
D
(NaCl): υ 1780 cm-1 (CdO); 1730 cm-1 (CO). 1H NMR (CDCl3,
δ ppm): 7.44-6.92 (m, 15H); 4.66 (d, 1H, J ) 5.9 Hz); 4.65 (d,
1H J ) 15.2 Hz); 4.48 (d, 1H, J ) 2.6 Hz); 4.48 (t, 1H, J ) 8.8
Hz); 4.24 (dd, 1H, J ) 6.6 Hz, J ) 8.8 Hz); 4.02 (d, 1H, J )
15.2 Hz); 3.96 (dd, 1H, J ) 6.6 Hz, J ) 8.8 Hz); 3.48 (dd, 1H,
J ) 2.6 Hz, J ) 5.8 Hz); 0.85 (s, 9H); -0.01 (s, 3H); -0.25 (s,
3H). 13C NMR (CDCl3, δ ppm): 164.8, 157.0, 140.1, 137.8,
135.4, 129.3, 128.9, 128.7, 128.4, 128.3, 128.1, 127.4, 126.8,
126.5, 75.6, 70.6, 62.2, 61.1, 58.9, 45.5, 25.8, 18.0, -4.5, -5.0.
cis-(3S,4S)-1-Ben zyl-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]ben zyl]-3-[(4S)-2-oxo-4-isop r op yloxa zolid in -3-yl]a ze-
tid in -2-on e (25b). The title compound was prepared from
the acid chloride 2b and the imine 7 following the general
procedure and was separated from the anti-Evans isomer by
flash column chromatography (silica gel 230-400 mesh, ethyl
acetate/hexane 1:7 as eluant): white solid recrystallized from
ethanol; yield 44%; mp 212-214 °C (ethanol). [R]25D ) -31.0°
(c ) 0.8, CH2Cl2). IR (KBr): υ 1752 cm-1 (CdO); 1748 cm-1
(CO). 1H NMR (DMSO-d6 at 90 °C, δ ppm): 7.41-7.22 (m,
10H); 5.37 (d, 1H, J ) 8.8 Hz); 4.77 (d, 1H, J ) 15.6 Hz); 4.63
(d, 1H, J ) 5.4 Hz); 4.46 (d, 1H, J ) 15.6 Hz); 4.26 (t, 1H, J )
cis-(3R,4R)-1-Ben zyl-4-[(1S)-[(ter t-bu tyld im eth ylsilyl)-
oxy]eth yl]-3-[(4R,5S)-1,5-d im eth yl-2-oxo-4-p h en ylim id a -
zolid in -3-yl]a zetid in -2-on e (33). The title compound was
prepared from the acid chloride 31 and the imine 4 following
the general procedure. The crude â-lactam was purified by
flash column chromatography (silica gel 230-400 mesh, ethyl
acetate/hexane 1:4 as eluant): syrup further purified by
preparative HPLC (ethyl acetate as eluant, 10 mL/min, tR
)
14.47 min); yield 80%. [R]25 ) -25.2° (c ) 1.0, CH2Cl2). IR
D
(NaCl): υ 1766 cm-1 (CdO); 1739 cm-1 (N-CO-N). 1H NMR
(CDCl3, δ ppm): 7.45-7.18 (m, 10H); 4.80 (d, 1H, J ) 15.3

9194 J . Org. Chem., Vol. 61, No. 26, 1996
Palomo et al.
Hz); 4.68 (d, 1H, J ) 8.9 Hz); 4.45-4.31 (m, 1H); 4.11 (d, 1H,
J ) 15.3 Hz); 4.09 (d, 1H, J ) 5.1 Hz); 3.92-3.78 (m, 1H);
3.29 (dd, 1H, J ) 8.1 Hz, J ) 5.1 Hz); 2.77 (s, 3H); 1.20 (d,
3H, J ) 6.2 Hz); 0.89 (s, 9H); 0.76 (d, 3H, J ) 6.5 Hz); 0.07 (s,
3H); 0.06 (s, 3H). 13C NMR (CDCl3, δ ppm): 167.4, 160.3,
135.6, 128.4, 128.3, 127.9, 127.2, 67.2, 64.4, 62.9, 61.6, 55.3,
45.7, 28.4, 25.8, 22.1, 17.8, 15.1, -3.2, -4.2.
(dd, 1H, J ) 5.6 Hz, J ) 8.1 Hz); 1.57 (d, 3H, J ) 7.0 Hz); 1.06
(d, 3H, J ) 6.1 Hz); 0.78 (s, 9H); -0.01 (s, 3H); -0.29 (s, 3H).
13C NMR (CDCl3, δ ppm): 164.6, 157.9, 140.8, 136.1, 129.6,
129.1, 128.2, 128.0, 126.7, 126.5, 70.0, 68.4, 64.6, 62.8, 59.8,
54.8, 25.9, 21.2, 19.8, 17.9, -3.8, -4.6. Anal. Calcd for
C28H38N2O4Si (494.7): C, 67.98; H, 7.74; N, 5.66. Found: C,
67.20; H, 7.65; N, 5.87.
cis-(3S,4S)-4-[(1R)-[(ter t-Bu tyld im eth ylsilyl)oxy]eth yl]-
3-[(4S)-2-oxo-4-ph en yloxazolidin -3-yl]-1-[(1S)-ph en yleth yl]-
a zetid in -2-on e (45). The title compound was prepared from
the acid chloride 2a and the imine 44 following the general
procedure and was separated from the anti-Evans isomer by
flash column chromatography (silica gel 230-400 mesh, ethyl
acetate/hexane 1:9 as eluant): white low-melting point solid;
yield 49%. [R]25D ) +2.3° (c ) 1.0, CH2Cl2). IR (KBr): υ 1746
cm-1 (CdO). 1H NMR (CDCl3, δ ppm): 7.52-7.26 (m, 10H);
4.97 (dd, 1H, J ) 7.1 Hz, J ) 9.0 Hz); 4.69 (t, 1H, J ) 9.0 Hz);
4.49 (q, 1H, J ) 7.1 Hz, J ) 9.0 Hz); 4.25 (d, 1H, J ) 5.2 Hz);
4.23 (dd, 1H, J ) 7.1 Hz, J ) 9.0 Hz); 4.30-4.08 (m, 1H); 3.53
(dd, 1H, J ) 5.2 Hz, J ) 7.1 Hz); 1.68 (d, 3H, J ) 7.1 Hz); 1.00
(d, 3H, J ) 6.2 Hz); 0.94 (s, 9H); 0.12 (s, 3H); 0.11 (s, 3H). 13C
NMR (CDCl3, δ ppm): 164.7, 157.3, 141.4, 137.1, 129.2, 129.0,
126.3, 127.1, 126.7, 126.2, 70.2, 67.0, 65.8, 60.2, 59.1, 55.6, 26.0,
25.7, 21.1, 20.6, 17.8, -3.5, -4.1. Anal. Calcd for C28H38N2O4-
Si (494.7): C, 67.98; H, 7.74; N, 5.66. Found: C, 67.56; H,
7.60; N, 5.43.
cis-(3R,4R)-1-Ben zyl-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]b en zyl]-3-[(4R,5S)-1,5-d im et h yl-2-oxo-4-p h en ylim i-
d a zolid in -3-yl]a zetid in -2-on e (35). The title compound was
prepared from the acid chloride 31 and the imine 5 following
the general procedure. The crude â-lactam was purified by
flash column chromatography (silica gel 230-400 mesh, ethyl
acetate/hexane 1:3 as eluant). The title compound was
obtained as a syrup after purification by preparative HPLC
(ethyl acetate as eluant, 10 mL/min, tR ) 12.48 min): yield
18%. [R]25 ) -57.1° (c ) 1.0, CH2Cl2). IR (NaCl): υ 1765
D
cm-1 (CdO); 1708 cm-1 (N-CO-N). 1H NMR (CDCl3, δ
ppm): 7.47-7.08 (m, 13H); 6.61-6.58 (m, 2H); 5.19 (d, 1H, J
) 8.8 Hz); 4.74 (d, 1H, J ) 9.1 Hz); 4.41 (d, 1H, J ) 15.1 Hz);
4.10 (d, 1H, J ) 5.0 Hz); 3.92-3.86 (m, 1H); 3.58 (dd, 1H, J )
5.0 Hz, J ) 8.8 Hz); 2.81 (s, 3H); 2.44 (d, 1H, J ) 15.1 Hz);
0.83 (s, 9H); 0.76 (d, 3H, J ) 6.5 Hz); 0.02 (s, 3H); -4.8 (s,
3H). 13C NMR (CDCl3, δ ppm): 167.4, 160.5, 142.5, 135.7,
135.5, 128.8, 128.6, 128.3, 128.2, 128.1, 127.1, 72.9, 63.5, 63.3,
62.5, 55.5, 44.3, 28.7, 25.8, 17.9, 15.5, -4.0, -4.9.
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Am in o
â-La cta m s. Gen er a l P r oced u r e A. A solution of the
â-lactam 23a or 24a (6 mmol) in THF/tert-butyl alcohol (33.4
mL, 10:1) was added to a cold (-78 °C) solution of lithium (0.49
g, 72 mmol) dissolved in liquid amonia (100 mL). The volume
ratio of THF/tert-butyl alcohol to liquid ammonia was ap-
proximately 1:3. After the solution was stirred for 3 min at
-78 °C, the excess lithium was quenched with powdered
ammonium chloride (12 equiv) and the ammonia was allowed
to distill from the reaction. The residual ammonia and solvent
were removed in vacuo, and the carbamate salt was disolved
in water and acidified briefly to pH 3 to effect carbamic
decomposition. To isolate the free amine, a pH adjustment to
10 was followed by extraction with methylene chloride (3 ×
70 mL) to give the 3-aminoazetidin-2-one.
Gen er a l P r oced u r e B. A solution of the â-lactam 41 or
45 (6 mmol) in THF/tert-butyl alcohol (33.4 mL, 10:1) was
added to a cold (-78 °C) solution of lithium (0.62 g, 90 mmol)
dissolved in liquid amonia (100 mL). The volume ratio of THF/
tert-butyl alcohol to liquid ammonia was approximately 1:3.
After the solution was stirred for 3 min at -78 °C, the excess
lithium was quenched with powdered ammonium chloride (15
equiv) and the ammonia was allowed to distill from the
reaction. The residual ammonia and solvent were removed
in vacuo, and the carbamate salt was disolved in water and
acidified briefly to pH 3 to effect carbamic decomposition. To
isolate the free amine, a pH adjustment to 10 was followed by
extraction with methylene chloride (3 × 70 mL) to give the
3-aminoazetidin-2-one.
cis-(3S,4S)-4-[(1R)-[(ter t-Bu tyld im eth ylsilyl)oxy]eth yl]-
3-[(4S)-2-oxo-4-ph en yloxazolidin -3-yl]-1-[(1R)-ph en yleth yl]-
a zetid in -2-on e (38). The title compound was prepared from
the acid chloride 2a and the imine 37 following the general
procedure. The crude â-lactam was purified by flash column
chromatography (silica gel 230-400 mesh, ethyl acetate/
hexane 1:3 as eluant): white solid recrystallized from ethanol;
yield 57%; mp 127-129 °C (ethanol). [R]25D ) +70.1° (c ) 1.0,
CH2Cl2). IR (KBr): υ 1748 cm-1 (CdO). 1H NMR (DMSO-d6
at 90 °C, δ ppm): 7.48-7.20 (m, 10H); 5.03 (dd, 1H, J ) 5.4
Hz); 4.72 (t, 1H, J ) 8.8 Hz); 4.54 (q, 1H, J ) 7.0 Hz); 4.45 (d,
1H, J ) 5.1 Hz); 4.16 (dd, 1H, J ) 5.4 Hz, J ) 8.8 Hz); 3.86
(m, 1H); 3.62 (dd, 1H, J ) 5.1 Hz, J ) 8.4 Hz); 1.50 (d, 3H, J
) 7.0 Hz); 1.12 (d, 3H, J ) 5.9 Hz); 0.73 (s, 9H); -0.08 (s, 3H);
-0.36 (s, 3H). 13C NMR (DMSO-d6 at 90 °C, δ ppm): 163.8,
158.3, 140.3, 138.1, 129.4, 129.3, 128.1, 127.9, 126.9, 126.7,
70.7, 69.2, 63.9, 59.9, 59.0, 54.7, 25.7, 20.1, 19.3, 17.7, -3.8,
-4.8. Anal. Calcd for C28H38N2O4Si (494.7): C, 67.98; H, 7.74;
N, 5.66. Found: C, 68.03; H, 7.59; N, 5.41.
cis-(3S,4S)-4-[(1R)-[(ter t-Bu tyld im eth ylsilyl)oxy]eth yl]-
3-[(4S)-2-oxo-4-ph en yloxazolidin -3-yl]-1-[(1S)-ph en yleth yl]-
a zetid in -2-on e (40). The title compound was prepared from
the acid chloride 2a and the imine 39 following the general
procedure. The crude â-lactam was purified by flash column
chromatography (silica gel 230-400 mesh, ethyl acetate/
hexane 1:4 as eluant) and the title compound was separated
from the anti-Evans isomer by preparative HPLC (ethyl
acetate as eluant, 10 mL/min, tR ) 9.48 min): syrup; yield 16%.
[R]25 ) +60.7° (c ) 1.6, CH2Cl2). IR (NaCl): υ 1752 cm-1
D
(CdO). 1H NMR (CDCl3, δ ppm): 7.48-7.24 (m, 10H); 4.94
(dd, 1H, J ) 7.0 Hz, J ) 9.0 Hz); 4.67 (t, 1H J ) 9.0 Hz); 4.61
(q, 1H, J ) 7.2 Hz); 4.25-4.17 (m, 1H); 4.20 (d, 1H, J ) 7.0
Hz, J ) 9.0 Hz); 4.13 (d, 1H, J ) 5.2 Hz); 3.39 (dd, 1H, J ) 5.2
Hz, J ) 7.5 Hz); 1.77 (d, 3H, J ) 7.2 Hz); 1.03 (d, 3H, J ) 6.2
Hz); 0.90 (s, 9H); 0.10 (s, 3H); 0.09 (s, 3H). 13C NMR (CDCl3,
δ ppm): 165.5, 157.6, 141.4, 137.5, 129.5, 129.3, 128.7, 127.5,
126.6, 71.5, 67.5, 63.8, 60.5, 59.7, 54.6, 25.9, 25.7, 21.9, 19.1,
-2.8, -3.4.
cis-(3R,4R)-3-Am in o-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]eth yl]a zetid in -2-on e (42). The title compound was
prepared from the the â-lactam 24a following the general
procedure A and from 41 following general procedure B and
was obtained as a syrup which was utilized in the next step
without further purification: yields 78% and 73%, respectively.
IR (NaCl): υ 3575-2980 cm-1 (NH2, NH); 1744 (CdO). 1H
NMR (CDCl3, δ ppm): 6.11 (sb, 1H); 4.19 (d, 1H, J ) 5.2 Hz);
3.96-3.81 (m, 1H); 3.47 (dd, 1H, J ) 5.2 Hz, J ) 7.0 Hz); 0.10
(s, 6H). 13C NMR (CDCl3, δ ppm): 171.5, 68.2, 61.1, 59.9, 29.6,
25.7, 17.9, 0.9, -3.6.
cis-(3S,4S)-3-Am in o-4-[(1R)-[(ter t-bu tyld im eth ylsilyl)-
oxy]eth yl]a zetid in -2-on e (47). The title compound was
prepared from the the â-lactam 23a following general proce-
dure A and from 45 following general procedure B: white solid
recrystallized from hexane; yields 79% and 75%, respectively;
mp 96-98 °C (hexane). [R]25D ) -51.3° (c ) 0.56, CH2Cl2). IR
(KBr): υ 3400-3100 cm-1 (NH); 1691 (CdO). 1H NMR (CDCl3,
δ ppm): 5.96 (sb, 1H); 4.21 (d, 1H, J ) 5.1 Hz); 4.14 (qd, 1H,
J ) 2.8 Hz, J ) 6.5 Hz); 3.57 (dd, 1H, J ) 2.8 Hz, J ) 5.1 Hz);
1.93 (sb, 1H); 1.31 (d, 3H, J ) 6.5 Hz); 0.88 (s, 9H); 0.07 (s,
9H). 13C NMR (CDCl3, δ ppm): 173.2, 68.8, 63.4, 58.6, 26.2,
cis-(3R,4R)-4-[(1R)-[(ter t-Bu tyldim eth ylsilyl)oxy]eth yl]-
3-[(4S)-2-oxo-4-ph en yloxazolidin -3-yl]-1-[(1S)-ph en yleth yl]-
a zetid in -2-on e (41). The title compound was prepared from
the acid chloride 2a and the imine 39 following the general
procedure. The crude â-lactam was purified by flash column
chromatography (silica gel 230-400 mesh, ethyl acetate/
hexane 1:3 as eluant) and the title compound was separated
from the Evans isomer by crystallization from ethanol: white
solid; yield 36%; mp 156-158 °C (ethanol). [R]25 ) +80.1° (c
D
) 1.0, CH2Cl2). IR (Nujol) υ 1749 cm-1 (CdO). 1H NMR
(CDCl3, δ ppm): 7.45-7.18 (m, 10H); 6.19 (q, 1H, J ) 7.0 Hz);
4.92 (t, 1H, J ) 8.4 Hz); 4.65 (t, 1H, J ) 8.4 Hz); 4.51 (d, 1H,
J ) 5.6 Hz); 4.50-4.43 (m, 1H); 4.27 (t, 1H, J ) 8.4 Hz); 3.54

Asymmetric Synthesis of â-Lactams
J . Org. Chem., Vol. 61, No. 26, 1996 9195
20.3, 18.3, -4.1, -4.5. Anal. Calcd for C11H24N2O2Si
(216.32): C, 54.05; H, 9.89; N, 11.46. Found: C, 53.97; H, 9.75;
N, 11.32.
sium derivative (3.9 mmol) was added dropwise to this solution
at -40 °C, and the reaction mixture was stirred for 1 h. Then
it was allowed to reach room temperature and stirred for an
additional 1 h, after which it was poured into NH4Cl (saturated
solution, 30 mL) and methylene chloride was added. The
aqueous layer was separated and extracted with methylene
chloride (30 mL). The organic layers were combined, washed
with water (30 mL), and dried over MgSO4. Evaporation of
the solvent under reduced pressure gave a crude which was
further purified by flash column chromatography (230-400
mesh, ethyl acetate/hexane 1:3 as eluant).
cis-(3R,4R)-1-Ben zyl-4-for m yl-3-[(4R)-2-oxo-4-p h en yl-
oxa zolid in -3-yl]a zetid in -2-on e (11). p-Toluensulfonic acid
monohydrate (0.63 g, 3.3 mmol) was added to a solution of the
â-lactam 10 (4.22 g, 10 mmol) in THF/water (100 mL, 2:1).
The resulting mixture was refluxed for 6 h and then basified
with a saturated solution of NaHCO3 to pH 7. The organic
layer was separated, and the aqueous layer was extracted with
ethyl acetate (2 × 30 mL). The organic layers were combined
and dried over MgSO4. Evaporation of the solvent under
reduced pressure gave a residue which was dissolved in
acetone/water (90 mL, 13:1). NaIO4 (8.56 g, 40 mmol) was
added in one portion to this solution cooled at 0-5 °C, and
the resulting suspension was stirred at the same temperature
for 1 h 30 min. Then the precipitated salts were filtered off,
and the filtrate was concentrated in vacuo. The residue was
diluted with methylene chloride (20 mL) and washed with
water (25 mL). The organic layer was dried over MgSO4, and
evaporation of the solvent under reduced pressure gave a crude
which was further purified by flash column chromatography
(silica gel 230-400 mesh, hexane and then ethyl ether as
Gen er a l P r oced u r e for th e Red u ction of 4-Acyl â-La c-
ta m s. A 1 M solution of L-Selectride in THF (3.4 mmol) was
added via syringe to a solution of the corresponding 4-acyl
â-lactam (1.7 mmol) in THF (10 mL) cooled at -78 °C. The
resulting mixture was stirred for 1 h at -60 °C, and then water
(2 mL) and ethyl ether (50 mL) were added. The mixture was
acidified with 6 M HCl, and the organic layer was separated
and dried over MgSO4. Evaporation of the solvents under
reduced pressure gave the correspondig hydroxy â-lactam.
cis-(3S,4S)-1-Ben zyl-4-[(1R)-h yd r oxyet h yl]-3-[(4S)-2-
oxo-4-p h en yloxa zolid in -3-yl]a zetid in -2-on e (51). The title
compound was prepared from 4-acetyl â-lactam 17a following
the general procedure. The crude â-lactam was purified by
flash column chromatography (silica gel 230-400 mesh, ethyl
acetate/hexane 1:2 as eluant). A white solid recrystallized
eluant) to afford a low-melting-point solid: yield 85%. [R]25
D
) -61.4° (c ) 0.56, CH2Cl2). IR (KBr): υ 1750 cm-1 (CdO).
1H NMR (CDCl3, δ ppm): 9.40 (d, 1H, J ) 2.2 Hz); 7.45-7.23
(m, 10H); 4.92 (t, 1H, J ) 8.6 Hz); 4.63 (t, 1H, J ) 8.6 Hz);
4.61 (d, 1H, J ) 15.4 Hz); 4.52 (d, 1H, J ) 15.4 Hz); 4.48 (d,
1H, J ) 5.7 Hz); 4.15 (t, 1H, J ) 5.7 Hz); 4.15 (t, 1H, J ) 8.6
Hz); 4.03 (dd, 1H, J ) 2.2 Hz, J ) 5.7 Hz). 13C NMR (CDCl3,
δ ppm): 198.0, 164.0, 157.6, 135.9, 132.2, 129.7, 129.6, 129.5,
129.1, 128.5, 127.5, 71.2, 63.9, 62.0, 60.4, 46.2. Anal. Calcd
for C20H18N2O4 (350.37): C, 68.56; H, 5.18; N, 7.99. Found:
C, 68.39; H, 5.04; N, 7.72.
from ethanol: yield 94%; mp 183-184 °C (ethanol). [R]25
)
D
+136.1° (c ) 1.0, CH2Cl2). IR (NaCl): υ 3468 cm-1 (OH); 1757
cm-1 (CO); 1723 cm-1 (CO). 1H NMR (CDCl3, δ ppm): 7.49-
7.08 (m, 10H); 5.13 (dd, 1H, J ) 7.5 Hz, J ) 9.0 Hz); 4.72 (t,
1H, J ) 9.0 Hz); 4.61 (d, 1H, J ) 15.5 Hz); 4.34 (d, 1H, J )
4.9 Hz); 4.24 (dd, 1H, J ) 7.5 Hz, J ) 9.0 Hz); 4.14 (d, 1H, J
) 15.5 Hz); 3.92-3.88 (m, 1H); 3.35 (dd, 1H, J ) 4.9 Hz, J )
8.8 Hz); 2.25-2.11 (sb, 1H); 1.10 (d, 3H, J ) 6.1 Hz). 13C NMR
(CDCl3, δ ppm): 165.1, 158.3, 137.3, 135.2, 129.3, 129.1, 128.7,
127.7, 127.6, 127.4, 70.9, 65.7, 63.2, 60.4, 60.3, 45.6, 22.0.
Anal. Calcd for C21H22N2O4 (366.42): C, 68.84; H, 6.05 N, 7.64.
Found: C, 68.71; H, 5.93; N, 7.42.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e cis-
(3S,4S)-1-Ben zyl-4-ca r boxy-3-[(4S)-2-oxo-4-p h en yloxa zo-
lid in -3-yl]a zet id in -2-on e (50). The same de-acetalization
procedure as above was followed starting from â-lactam 49
(2.36 g, 5.6 mmol). Then, NaIO4 (3.2 g, 1.5 mmol) and KMnO4
(0.4 g, 2.5 mmol) were added to a suspension of the crude diol
in acetone/water (65 mL/62.5 mL). The resulting mixture was
stirred at room temperature for 2 h. Then water (100 mL)
was added, and NaHSO3 (40% solution, 35 mL) was added
dropwise maintaining the temperature between 0 and 5 °C.
The resulting yellow solution was extracted with ethyl acetate
(2 × 100 mL). The organic layer was washed with NaHCO3
(saturated solution, 2 × 100 mL), and the aqueous layers were
combined, acidified, and extracted with ethyl acetate (2 × 100
mL). The combined organic solutions were dried over MgSO4,
and the evaporation of the solvent under reduced pressure
gave a crude which was then purified by flash column
chromatography (silica gel 230-400 mesh, methylene chloride/
hexane 4:1 as eluant and then methylene chloride/methanol
cis-(3S,4S)-1-Ben zyl-4-[(1R)-h yd r oxyben zyl]-3-[(4S)-2-
oxo-4-p h en yloxa zolid in -3-yl]a zetid in -2-on e (52). The title
compound was prepared from 4-benzoyl â-lactam 18a following
the general procedure. The crude â-lactam was purified by
flash column chromatography (silica gel 230-400 mesh, ethyl
acetate/hexane 1:2 as eluant). A white solid recrystallized
from ethanol: yield 98%; mp 175-177 °C (ethanol). [R]25
)
D
+145.9° (c ) 1.0, CH2Cl2). IR (KBr): υ 3363 cm-1 (OH); 1754
cm-1 (CO); 1748 cm-1 (CO). 1H NMR (DMSO-d6, δ ppm):
7.55-7.17 (m, 13H); 6.64 (d, 2H); 5.89 (db, 1H); 5.08 (dd, 1H,
J ) 6.8 Hz, J ) 8.8 Hz); 4.80 (t, 1H, J ) 8.8 Hz); 4.32 (d, 1H,
J ) 4.9 Hz); 4.19 (d, 1H, J ) 15.4 Hz); 4.19 (dd, 1H, J ) 6.8
Hz, J ) 8.8 Hz); 3.69 (dd, 1H, J ) 4.9 Hz, J ) 9.1 Hz); 3.02 (d,
1H, J ) 15.4 Hz). 13C NMR (DMSO-d6, δ ppm): 165.3, 157.5,
143.2, 138.5, 135.6, 129.5, 129.1, 128.8, 128.5, 128.3, 127.6,
127.4, 126.6, 71.6, 70.4, 62.2, 60.8, 60.1, 44.5. Anal. Calcd
for C26H24N2O4 (428.49): C, 72.88; H, 5.64; N, 6.54. Found:
C, 72.75; H, 5.57; N, 6.38.
9:1) to afford a low-melting-point white solid: yield 59%. [R]25
D
) +119.2° (c ) 1.0, CH2Cl2). IR (KBr): υ 3250-2750 cm-1
(OH); 1759 cm-1 (CO); 1754 cm-1 (CO). 1H NMR (DMSO-d6
at 90 °C, δ ppm): 7.49-7.37 (m, 5H); 7.31-7.23 (m, 5H); 4.96
(t, 1H, J ) 8.6 Hz); 4.70 (d, 1H, J ) 15.5 Hz); 4.68 (t, 1H, J )
8.6 Hz); 4.49 (d, 1H, J ) 5.6 Hz); 4.31 (d, 1H, J ) 15.5 Hz);
4.20 (d, 1H, J ) 5.6 Hz); 4.12 (t, 1H, J ) 8.6 Hz). 13C NMR
(DMSO-d6 at 90 °C, δ ppm): 170.2, 164.4, 156.9, 137.7, 135.8,
129.3, 129.0, 128.6, 128.0, 127.5, 127.4, 70.5, 60.6, 60.0, 56.0,
44.7. Anal. Calcd for C20H18N2O5 (366.37): C, 65.57; H, 4.95;
N, 7.65. Found: C, 65.32; H, 4.81; N, 7.59.
Ack n ow led gm en t. Financial support of this work
by Comisio´n Interministerial de Ciencia y Tecnolog´ıa
(Project SAF 95/0749). A grant from Gobierno Vasco
to A.M. is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Spectral and ana-
lytical data (1H NMR, 13C NMR, IR, MS) are provided for
compounds 12, 15a -c, 16a , 17a -c, 18a , 20, 21, 22, 27a , 27c,
28a , 43, and 48 (6 pages). This material is contained in
libraries on microfiche, inmediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current mastahead page for ordering information.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 4-Acyl
â-La cta m s. Thionyl chloride (4.5 mL, 6 mmol) was added to
a solution of the 4-carboxy â-lactam (3.1 mmol) in dry meth-
ylene chloride (15.5 mL). The resulting mixture was refluxed
for 3 h, and evaporation of the solvent under reduced pressure
gave a solid residue which was then disolved in dry THF (15
mL). A 3.0 M solution in Et2O of the corresponding magne-
J O9612180