A new synthetic approach for novel C-3 substituted β-lactams

Article abstract of DOI:10.1016/S0040-4039(00)00865-0

An effective route to novel C-3 substituted β-lactams is described. This involves reaction of a β-lactam carbocation equivalent with active aromatic nucleophiles in the presence of a Lewis acid. The stereo-specificity of the formation of mono-substituted products may be rationalised on the basis of the SnCl₄ mediated intermediate complex A that reacts via an S(N)2 mechanism. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00865-0

Tetrahedron Letters 41 (2000) 5577±5581
A new synthetic approach for novel C-3 substituted b-lactams
Sachin Madan, Renu Arora, P. Venugopalan and S. S. Bari*
Department of Chemistry & Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160 014, India
Received 13 March 2000; accepted 23 May 2000
Abstract
An e€ective route to novel C-3 substituted b-lactams is described. This involves reaction of a b-lactam
carbocation equivalent with active aromatic nucleophiles in the presence of a Lewis acid. The stereo-
speci®city of the formation of mono-substituted products may be rationalised on the basis of the SnCl4
mediated intermediate complex A that reacts via an SN2 mechanism. # 2000 Elsevier Science Ltd. All
rights reserved.
b-Lactams are well-acknowledged structural elements of the widely used penicillins, cephalo-
sporins, thienamycins and other monocyclic b-lactam antibiotics1 such as monobactams. New
routes for the synthesis of monocyclic b-lactams with di€erent appendages at C-3 and C-4 con-
tinue to present a challenge for the synthetic organic chemist. More recently, C-3 aryl substituted
monocyclic b-lactams have been shown to be potential inhibitors of cholesterol acyl transferase2
which is mainly responsible for atherosclerotic coronary heart disease.
Transformations at the C-3 carbon of b-lactams leading to the formation of diverse molecules
involving anionic and cationic b-lactam equivalents 1 and 2, respectively (Fig. 1) are an important
area of research.3 The potential of the anionic b-lactam equivalent of type 1 has been explored by
many groups4 for the preparation of di€erent b-lactam synthons.
Figure 1.
However, the chemistry involving the cationic b-lactam equivalent 2 is not fully explored. A
related study involving SN20 substitution at C-3 has recently been reported.5 Hence, our attention
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00865-0

5578
was focused on the use of the cationic b-lactam equivalent type 2 and the exploration of its
potential in synthetically useful transformations. We report here a new strategy for the synthesis
of novel C-3 substituted b-lactams involving an easily available6 a-chloro-a-phenylthio-b-lactam
6. This b-lactam is capable of functioning as a C-3 carbocation equivalent in the presence of a
Lewis acid.
Thus, in the presence of the Lewis acid7 SnCl4, b-lactam 6 reacts with a number of active aromatic
nucleophiles to produce a variety of substituted b-lactams. A number of interesting C-3 mono-
substituted as well as disubstituted b-lactams which may not be easily prepared via the classical
routes using an acid chloride-imine cycloaddition8 approach, are accessible using this strategy
(Scheme 1).
Scheme 1.
b-Lactams 5, suitable for this study, were prepared from potassium phenylthioacetate 3 and
appropriate Schi€ bases 4 by the reported procedure.6 These b-lactams 5 were converted to the
corresponding 3-chloro-3-phenylthioazetidin-2-ones 6(a±c) by reacting with SO2Cl2.9 Initial studies
were carried out by reacting 6a with anisole as the nucleophile10 in the presence of 1 equivalent of
SnCl4 at ^78ꢀC. Instead of leading to the formation of the expected monosubstituted product of
type 7, surprisingly, the product was found to be a mixture of two compounds. These products,
after chromatographic puri®cation, were identi®ed as 3,3-bis(4-methoxyphenyl)-1-(4-methoxy-
phenyl)-4-phenylazetidin-2-one 8a and 3,3-bis(phenylthio)-1-(4-methoxyphenyl)-4-phenylazetidin-2-
one 9a on the basis of their spectroscopic data and by X-ray crystallography. The reaction was
found to be general for several active aromatic nucleophiles and the results obtained are summarised
in Table 1.

5579
Table 1
Reaction of cationic b-lactam equivalents 6 with various active aromatic nucleophiles using SnCl4 as Lewis acid
Most of the activated aromatic nucleophiles produce the 3,3-disubstituted azetidin-2-ones of
type 8, along with varying amounts of 3,3-diphenylthioazetidin-2-ones of type 9. However, it is
interesting to note that the monosubstituted products of type 7 were formed along with disub-
stituted ones in the case of b-lactams 6a and 6c (entries 3, 8 and 9). The spatial juxtaposition of
the C-4 hydrogen and nucleophile at C-3 in 7a was assigned trans on the basis of its transformation
to the cis-b-lactam (J=6.2 Hz, C3-H and C4-H) on stereospeci®c11 Raney-nickel desulphurisation.
This was further con®rmed by the X-ray crystallographic analysis12 of monosubstituted b-lactam
7a (Fig. 2).
Figure 2. Ortep representation of 7a
The same result was established for 7c via its Raney-nickel desulphurisation leading to the
formation of cis-b-lactam 10 (Scheme 2) (J=5.6 Hz, C3-H and C4-H). Similarly, 11c also produced
the cis-b-lactam on desulphurisation. The reaction proceeds well in CH2Cl2 at ^78 to ^5ꢀC using 1
equivalent of SnCl4.

5580
Scheme 2.
It is interesting to note that the monosubstituted products are formed by approach of the
nucleophile to the more hindered face of the b-lactam. A possible explanation is that the Lewis
acid forms complex A (Scheme 1) thus preventing the approach of the incoming nucleophile from
the same side. The reaction probably follows Path A and proceeds via an SN2 mechanism. The
intermediate formation of carbocation B would have led to the opposite con®guration of b-lactams
7a and 7c. This is supported by the fact that benzene and toluene, being milder nucleophiles,
failed to react to give corresponding products.
The possible role of 7 as an intermediate in the formation of the disubstituted products 8 was
supported by the conversion of monosubstituted b-lactam 7c, into the disubstituted b-lactam 8c
on treatment with anisole, in the presence of SnCl4.
The formation of 9a (Scheme 1) was totally unexpected. The ambiphilic behaviour of -SPh as a
leaving group (leading to 8) and at the same time acting as a nucleophile (leading to 9) is
remarkable. The role of SnCl4 in these processes as a complexing agent may be involved (complex
A) and 9 may be formed by the approach of the nucleophilic -SPh from the opposite side to the
Lewis acid in complex A. However, the exact mechanism may be quite complex. Further studies
using heterocycles and trimethyl silyl enol ethers as nucleophiles are in progress in our laboratory.
In summary, the reaction of a b-lactam cation equivalent 6 with active aromatic nucleophiles
provides access to novel C-3 monocyclic substituted b-lactams. The starting b-lactams are easily
available and the reaction procedure, workup and the product puri®cation are also easy to carry
out.
Acknowledgements
We thank the Department of Science and Technology, Government of India, for ®nancial
support of this work, Grant No. SP/S1/G-29/94 and Professor S. V. Kessar, Senior Scientist,
Indian National Science Academy (INSA) for helpful discussions.
References
1. (a) Durckheimer, W.; Blumbach, J.; Lattrell, R.; Scheunemann, K. H. Angew. Chem., Int. Ed. Engl. 1985, 24, 180.
(b) Chu, D. T. W.; Plattner, J. J.; Katz, L. J. Med. Chem. 1996, 39, 3853. (c) Morin, R. B.; Gorman, M., Eds.;
Chemistry and Biology of ꢀ-Lactam Antibiotics; Academic Press: New York, 1982.
2. Burnett, D. A.; Caplen, M. A.; Davis Jr., H. R.; Burrier, R. E.; Clader, J. W. J. Med. Chem. 1994, 37, 1733.

5581
3. (a) Wild, H. In The Organic Chemistry of ꢀ-Lactams; Georg, G. I., Ed.; VCH: New York, 1992; pp. 53±64. (b)
O'Donnell, M. J.; Bennett, W. D. Tetrahedron 1988, 44, 5389.
4. (a) d'Angelo, J.; Pecquet-Dumas, F. Tetrahedron Lett. 1983, 24, 1403. (b) Roe, J. M.; Thomas, E. J. Synlett 1990,
727. (c) Yamashita, H.; Minami, N.; Sakakibara, K.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1988, 36, 69.
[DOC1]
5. (a) Bellettini, J. R.; Miller, M. J. J. Org. Chem. 1996, 61, 7959. (b) Teng, M.; Miller, M. J. J. Am. Chem. Soc. 1993,
115, 548.
6. van der Veen, J. M.; Bari, S. S.; Krishnan, L.; Manhas, M. S.; Bose, A. K. J. Org. Chem. 1989, 54, 5758.
7. Arai, K.; Ohara, Y.; Iizumi, T.; Takakuwa, Y. Tetrahedron Lett. 1983, 24, 1531.
8. Manhas, M. S.; van der Veen, J. M.; Wagle, D. R.; Hegde, V. R.; Bari, S. S.; Kosarych, Z.; Ghosh, M.; Krishnan,
L. Indian J. Chem. 1986, 25B, 1095.
9. Chu, D. T. W. J. Org. Chem. 1983, 48, 3571.
10. General procedure for the synthesis of 8a: To a stirred mixture of 3-chloro-3-phenylthioazetidin-2-one 6a (80 mg,
0.2 mmol) and anisole (0.02 mL, 0.2 mmol) in dry methylene chloride (10 mL) cooled at ^78ꢀC was added SnCl4
(0.026 mL, 0.22 mmol) rapidly under a nitrogen atmosphere and the resulting solution was stirred for an
additional 2 h at the same temperature. The reaction mixture was cooled to rt, quenched with water, extracted
with methylene chloride, washed with a 5% NaHCO3 solution, dried over MgSO4 and then puri®ed using column
chromatography (15% EtOAc±hexanes). The product was recrystallised from CH2Cl2/hexanes to furnish colorless
crystals of 8a (44 mg, 47%), mp 136±138ꢀC; FTIR (KBr) 1736 cm^1; 1H NMR (300 MHz, CDCl3) ꢁ 7.54±6.53 (m,
17H), 5.67 (s, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.65 (s, 3H); 13C NMR (300 MHz, CDCl3) ꢁ 167.05, 158.80, 158.15,
156.12, 135.18, 133.36, 131.16, 129.74, 129.56, 128.43, 128.39, 128.10, 127.65, 118.78, 114.28, 114.15, 113.25, 71.23,
67.57, 55.43, 55.34, 55.08; MS (EI): 465.5397 M+.
11. Ireland, R. E.; Marshall, J. A. J. Org. Chem. 1962, 27, 1615.
12. Crystal data for [C33H27NO3S]: MW=517.62, monoclinic, P21/c, a=10.546(1) A, b=21.341(2) A, c=12.501(1) A,
ꢀ=108.60(1)ꢀ, V=2666.5(4) A3, Z=4, T=293(2) K, ꢂ(Mo-Ka)=1.57 cm^1, Dcalcd=1.289 mg/m3, re®nement on
F2, R1=0.0407 and wR2=0.1115 for 3655 observed re¯ections [I>2ꢃ(I)].