An asymmetric synthesis of β-lactams: On the use of chiral oxazolidones in the Kinugasa reaction

Article abstract of DOI:10.1016/S0040-4039(02)00974-7

Enantiopure cis and trans β-lactams 3a-e and 4a-e, respectively, have been synthesized via cycloaddition between chiral oxazolidinyl propynes 1a-b and nitrones 2a-d, in the presence of cuprous iodide (the Kinugasa reaction).

Full text of DOI:10.1016/S0040-4039(02)00974-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5499–5501
An asymmetric synthesis of b-lactams: on the use of chiral
oxazolidones in the Kinugasa reaction
Amit Basak,a,* Subhash C. Ghosh,a Tandra Bhowmick,a Amit K. Dasb and Valerio Bertolasic
aDepartment of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
bDepartment of Biotechnology, Indian Institute of Technology, Kharagpur 721302, India
cDipartimento di Chimica, Universita di Ferrara via L. Borsanio, 46, 44100 Ferrara, Italy
Received 4 March 2002; revised 7 May 2002; accepted 17 May 2002
Abstract—Enantiopure cis and trans b-lactams 3a–e and 4a–e, respectively, have been synthesized via cycloaddition between chiral
oxazolidinyl propynes 1a–b and nitrones 2a–d, in the presence of cuprous iodide (the Kinugasa reaction). © 2002 Published by
Elsevier Science Ltd.
Although first synthesized by Staudinger1 way back in
1907, b-lactams as a class acquired importance only
after it was established that penicillin contains this unit
as a unique structural feature. Since then, several other
naturally occurring b-lactams have been isolated and
synthesized.2 Apart from their antibacterial properties,
b-lactams also show biological activities that include
inhibition of cholesterol absorption3 and human leuko-
cyte elastase (HLE).4 More recently, b-lactams have
been recognized as useful chiral starting materials for
the synthesis of natural and unnatural products.5 Enan-
tiomerically pure b-lactams have been shown to be
versatile intermediates for the synthesis of aromatic
amino acids, oligopeptides and azetidines.6 The use of
monocyclic b-lactams as a synthon for the synthesis of
the side chain of taxol7 has solved a challenging prob-
lem in the synthesis of taxol from baccatin. Thus any
new synthesis that produces homochiral b-lactams is
important in its own right and hence, not surprisingly,
the interest in b-lactam synthesis continues unabated
and several methods have been developed recently,
culminating in stereospecific syntheses of b-lactams
with requisite functionality.8 The most important of
these methods is obviously the ketene–imine cycloaddi-
tion (the Staudinger reaction), which is versatile
because of the availability of a wide range of imines
and ketenes.9 Several asymmetric syntheses via ketene–
imine cycloadditions are known.10 On the other hand,
the asymmetric version of the Kinugasa reaction,11
which involves the cycloaddition between an in situ
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00974-7

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A. Basak et al. / Tetrahedron Letters 43 (2002) 5499–5501
generated cuprous acetylide and a nitrone leading to a
b-lactam (usually a mixture of cis and trans) has not
been very successful. Miura et al.12 achieved an enan-
tiomeric excess of 40–60% by employing a C2-symmet-
ric oxazoline as a chiral ligand for copper. In this
paper, we report a chiral auxiliary based approach to
the Kinugasa reaction that proceeds with high
enantiospecificity.
proceeds through an intramolecularly chelated copper
complex (as shown in A).
Evan’s chiral oxazolidinyl acid chloride10a has been
employed as a ketene synthon to bring about a high
degree of asymmetric induction in the Staudinger reac-
tion. A similar strategy may be adopted in the case of
the Kinugasa reaction by using a homochiral N-propar-
gyl oxazolidinone. It was hoped that the oxazolidinone
side chain would then control the approach of the
nitrone. Intermediate B having the substituents (benzyl
and R) on opposite faces should be of lower energy as
compared to intermediate C where the substituents are
on the same face. Thus there will be a preference for the
chirality at C-4 of the resulting isooxazoline. This, in
turn, will fix the chirality at C-3 of the cis and the trans
azetidinone; the latter has already been shown13 to
originate from the cis diastereomer, via epimerization.
To induce asymmetry in the Kinugasa reaction, there
are three options: use a chiral (a) nitrone or (b) acetyl-
ene or (c) a ligand designed for chelation to copper. All
these three approaches rely on the generation of
diastereomeric transition states that differ in energy by
a substantial amount so as to effect a high degree of
asymmetric induction. Miura’s approach of using an
external chiral ligand resulted in mixed success. It
occurred to us that the degree of induction might
improve if the ligand is crafted on to one of the
components, namely the acetylene so that the reaction
The requisite (4S)-benzyl-3-propargyl oxazolidone 1a
was prepared in 60% overall yield from (S)-phenylala-
nine as shown in Scheme 1. The N-alkylation was
carried out with propargyl bromide in the presence of
K2CO3 and DMF. For unknown reasons, 1a was not
very stable at room temperature. However, it can be
stored in the refrigerator for extended periods of time
without much decomposition. The reactions of 1a with
various nitrones in the presence of cuprous iodide were
Scheme 1.
Table 1. Cycloaddition of 1a–b with nitrones (2a–d)
Acetylene
component
Nitrone
Ratio of trans and cis Combined
Compound no./mp/specific
rotationa of cis b-lactams
Compound no./mp/specific
rotationa of trans b-lactams
b-lactams
yield (%)
1a
1a
1a
1a
1b
1b
1b
2a
2b
2c
2d
2a
2b
2c
3:2
5:4
5:4
5:3
3:1
3:1
3:1
65
63
65
70
65
62
63
3a/160–162°C/(+) 131
3b/144–145°C/(+) 54.4
3c/161–163°C/(+) 98.6
3d/140–142°C/(+) 55.9
3e/210–212°C/(+) 195.8
3f/192–193°C/(+) 181.7
3g/165–166°C/(+) 181.7
4a/158–160°C/(−) 37.3
4b/95–98°C/(−) 65.1
4c/120–122°C/(−) 23.5
4d/55–57°C/(−) 7.9
4e/192–194°C/(−) 45.7
4f/185–186°C/(−) 43.1
4g/202–203°C/(−) 38.5
a Rotations were recorded in CHCl3 at 27°C. General procedure: To a solution of 1a in DMF under argon at 0°C, triethylamine (1 equiv.) was
added and the mixture stirred for 30 min. Cuprous iodide (1 equiv.) was added and the solution was stirred for another 5 min at 0°C after which
a DMF solution of the nitrone (0.75 equiv.) was added slowly over 5 min. After stirring for another 30 min at 0°C, the reaction was stirred at
room temperature for 16 h. The mixture was diluted with water and filtered through celite. The celite bed was washed with ethyl acetate. The
combined filtrate and washings were extracted with ethyl acetate. The residue, obtained after evaporation, upon chromatography afforded a
mixture of a single trans and single cis diastereomer. These two were easily separable by conventional chromatography over silica gel using
hexane/ethyl acetate (4:1) as eluent.

A. Basak et al. / Tetrahedron Letters 43 (2002) 5499–5501
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1
carried out; the H NMR spectra of the crude reaction
mixtures showed the presence of one cis and one trans
diastereomer which were easily separated by column
chromatography. The purity of the diastereomers was
Acknowledgements
The author (A.B.) thanks the Department of Science
and Technology, Government of India for financial
assistance.
revealed by their H and 13C NMR spectra with only
1
one set of signals being present even in the presence of
a chiral shift reagent [Eu(fod)3]. As is evident from the
data provided in Table 1, these reactions proceeded in
good yields and exhibited excellent levels of stereo-
chemical control. They have the added advantage of
providing greater than 95% asymmetric induction in
both the cis and trans product manifold. The reactions
also worked with the same efficiency in the case of the
easily removable10a oxazolidine 1b, derived from S-
phenylglycine. In the presence of a catalytic amount of
CuI, the reaction was slow and required an excess of
nitrone (>2 equiv.) to give similar yields and selectivity
as observed using stoichiometric amounts of CuI.
Nitrones derived from aliphatic aldehydes failed to
provide decent yields of b-lactams.
References
1. Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51.
2. (a) Chemistry and Biology of i-Lactam Antibiotics;
Morin, R. B.; Gorman, M., Eds.; Academic Press: New
York, 1982; Vols. 1–3; (b) The Chemistry of i-Lactams;
Page, M. I., Ed.; Chapman Hall: New York, 1992.
3. (a) Burnett, D. A.; Caplen, M. A.; Davis, H. R., Jr.;
Burrier, R. E.; Clader, J. W. J. Med. Chem. 1994, 37,
1733; (b) Dugar, S.; Yumibe, N.; Clader, J. W.; Vizzi-
ano, M.; Huie, K.; van Heek, M.; Compton, D. S.;
Davis, H. R., Jr. Bioorg. Med. Chem. Lett. 1996, 6,
1271.
4. Doherty, J. B.; Ashe, B. M.; Agrenbright, L. W.;
Barker, P. L.; Bonney, R. J.; Chandler, G. O.;
Dahlgren, M. E.; Dorn, C. P., Jr.; Finke, P. E.; Fire-
stone, R. A.; Fletcher, D.; Hagemann, W. K.; Munford,
R.; O’Grady, L.; Maycock, A. L.; Pisano, J. M.; Shah,
S. K.; Thomson, K. R.; Zimmerman, M. Nature 1986,
322, 192.
The absolute stereochemistry of one of the compounds,
4c, was determined by single crystal X-ray diffraction
(Fig. 1). The absolute configuration (3R,4S) of the
structure was determined, as indicated by the Flack
parameter14 of −0.07 and is in accordance with our
prediction. Although it had been reported by Ding and
Irwin that the trans compounds originated from the cis
isomers by epimerization under basic conditions, we
also demonstrated that this was indeed true. Thus, the
trans isomer 4b could be obtained from the cis isomer
3b by treatment with n-BuLi at −20°C followed by
quenching with NH4Cl.
5. The Organic Chemistry of i-Lactams; Georg, G. I., Ed.;
VCH: Weinheim, 1993.
6. Ojima, I. In The Organic Chemistry of i-Lactams;
Georg, G. I., Ed.; VCH, 1993; p. 197.
7. Farina, V. The Chemistry and Pharmacology of Taxol
and its Derivatives I; Elsevier: New York, 1995.
8. (a) Wu, G. Org. Proc. R & D 2000, 4, 298; (b) Wu, G.;
Wong, Y.; Chen, X.; Ding, Z. J. Org. Chem. 1999, 64,
3714; (c) Fujieda, H.; Kanai, M.; Kambara, T.; Tida,
A.; Tomioka, K. J. Am. Chem. Soc. 1997, 119, 2060; (d)
Process Chemistry in Pharmaceutical Industry; Gadama-
setti, K. G., Ed.; Marcel Dekker: New York, 1999; p.
221.
9. (a) Manhas, M. S.; Amin, S. G.; Bose, A. K. Heterocy-
cles 1976, 5, 669; (b) Carroll, R. D.; Reed, L. L. Tetra-
hedron Lett. 1975, 3435; (c) Skiles, J. W.; McNeil, D.
Tetrahedron Lett. 1990, 31, 7277.
10. (a) Evans, D. A.; Sjorgren, E. B. Tetrahedron Lett. 1985,
26, 3783; (b) Boger, D. L.; Myers, J. B. J. Org. Chem.
1991, 56, 5385; (c) Cooper, R. D. G.; Daugherty, B. W.;
Boyd, D. B. Pure Appl. Chem. 1987, 59, 485; (d) Georg,
G. I.; Ravikumar, V. T. In The Organic Chemistry of
i-Lactams; Georg, G. I., Ed.; VCH: Weinheim, 1993;
pp. 296–368.
11. Kinugasa, M.; Hashimoto, S. J. Chem. Soc., Chem.
Commun. 1972, 466–467.
12. Miura, M.; Enna, M.; Okura, K.; Nomura, N. J. Org.
Chem. 1995, 60, 4996.
13. Ding, L. K.; Irwin, W. J. J. Chem. Soc., Perkin Trans. 1
1976, 2382–2386.
14. Flack, H. D. Acta Crystallogr. 1983, A39, 876–881.
Figure 1. ORTEP diagram of 4c.