An efficient synthesis of N-benzyl-3-sulfonyl glutarimides. Formal synthesis of the aromatase inhibitor AG-1

Article abstract of DOI:10.1016/S0040-4039(00)01845-1

A formal [3+3] cycloaddition strategy to substituted glutarimides was studied. N-Benzyl α-sulfonylacetamides and various α,β-unsaturated esters were used as starting materials. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01845-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10273–10276
An efficient synthesis of N-benzyl-3-sulfonyl glutarimides.
Formal synthesis of the aromatase inhibitor AG-1
Meng-Yang Chang, Bo-Rui Chang, Huo-Mu Tai and Nein-Chen Chang*
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, ROC
Received 22 June 2000; revised 9 October 2000; accepted 19 October 2000
Abstract
A formal [3+3] cycloaddition strategy to substituted glutarimides was studied. N-Benzyl a-sulfonyl-
acetamides and various a,b-unsaturated esters were used as starting materials. © 2000 Elsevier Science
Ltd. All rights reserved.
Glutarimides possess various biological activities.1 Therefore, the preparation of these cyclic
imides has attracted considerable attention from organic chemists.2 We wish to report an efficient
route towards the synthesis of N-benzyl-3-sulfonyl-4-or-5-substituted glutarimides 1. The aro-
matase inhibitor AG-1 was also synthesized.3
Sequential treatment of chloroacetyl chloride with benzylamine and sodium p-toluenesulfinate
furnished a-toluenesulfonyl acetamide 3 in 90% yield. After reaction of 3 with two equivalents
of sodium hydride, the resulting dianion 4 reacted with a variety of a,b-unsaturated esters to afford
the corresponding substituted N-benzyl-3-toluenesulfonyl glutarimides 1. Presumably, after
1,4-addition, ring closure of 5 could then follow, providing the cyclized product 1 (Scheme 1).
Scheme 1.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01845-1

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As summarized in Table 1, using this protocol, various 4- or 5-alkyl- or aryl-N-benzyl-3-tolue-
nesulfonyl glutarimides were produced in moderate to excellent yields. More significantly, the
presence of the sulfonyl group differentiates between C3 and C5 in 1 therefore allowing
subsequent regioselective nucleophilic substitution. The carbonyl groups can be further elabo-
rated making possible the introduction of different substituents at C2 and C6. We have
successfully transformed 19 into 244 (Scheme 2), which has been converted to AG-1,3d an
efficient aromatase inhibitor and effective drug against breast cancer for postmenopausal
patients.5
Table 1
[3+3] Reaction of dianion 4 with various Michael acceptorsa,b,c
a All the yields were based on acetamide 3.
b The structures of 9 and 13 were confirmed by X-ray analysis.
c For selected NMR spectral data for 7, 15, 19, 22, 23, 24 see Ref. 6.
In conclusion, we have explored a formal [3+3] cycloaddition strategy that is synthetically
useful for constructing 4- or 5-substituted-3-toluenesulfonylglutarimides. We are currently
studying the scope of this process as well as additional applications of the methodology to the
synthesis of piperidines, indolizidines, quinolizidines and indoles.

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Scheme 2.
Acknowledgements
The authors would like to thank the National Science Council of the Republic of China for
financial support.
References
1. (a) Moreia, A. L.; Corral, L. G.; Ye, W.; Johnson, B. A.; Stirling, D.; Muller, G. W.; Freedman, V. H.; Kaplan,
G. AIDS Res. Hum. Retoviruses 1997, 13, 857. (b) Dawson, N.; Figg, W. D.; Brawley, O. W.; Bergan, R.; Cooper,
M. R.; Senderowicz, A.; Headlee, D.; Steinberg, S. M.; Sutherland, M.; Patronas, N.; Sausville, E.; Linehan, W.
M.; Reed, E.; Sartor, O. Chin. Cancer Res. 1998, 4, 37. (c) Waelbroeck, M.; Lazareno, S.; Plaff, O.; Friebe, T.;
Tastoi, M.; Mutschler, E.; Lambert, G. Br. J. Pharmacol 1996, 119, 1319. (d) Park, M.; Lee, J.; Choi, J. Bioorg.
Med. Chem. Lett. 1996, 6, 1297.
2. (a) Nazar, F.; Pham-Huy, C.; Galons, H. Tetrahedron Lett. 1999, 40, 3697. (b) Leung, C. S.; Rowlands, M. G.;
Jarman, M.; Foster, A. B.; Griggs, L. J.; Wilman, D. E. V. J. Med. Chem. 1987, 30, 1550. (c) Knabe, J.; Wahl, S.
Arch. Pharm. 1987, 330, 1032. (d) Polonski, T. J. Chem. Soc., Perkin Trans. 1 1988, 639. (e) Kim, M. H.; Patel,
D. V. Tetrahedron Lett. 1994, 35, 5603. (f) Robin, S.; Zhu, J.; Galons, H.; Pham-Huy, C.; Claude, J. R.; Tomas,
A.; Viossat, B. Tetrahedron: Asymmetry 1995, 6, 1249. (g) Zhu, J.; Pham-Huy, C.; Lemoine, P.; Tomas, A.;
Galons, H. Heterocycles 1996, 43, 1923.
3. (a) Bushell, S. M.; Crump, J. P.; Lawrence, N. J.; Pineau, G. Tetrahedron 1998, 54, 2269. (b) Achmatowicz, O.;
Malinowska, I.; Szechner, B.; Maurin, J. K. Tetrahedron 1997, 53, 7917. (c) Fadel, A.; Garciaargote, S.
Tetrahedron: Asymmetry 1996, 7, 1159. (d) Fogliato, G.; Fronza, G.; Fuganti, C.; Grasselli, P.; Servi, S. J. Org.
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1
4. The H and 13C NMR spectra of 24, in agreement with the literature,3d prove the regioselectivity of alkylation of
19.
5. (a) Hartmann, R. W.; Batzl, C.; Pongratz, T. M.; Mannschreck, A. J. Med. Chem. 1992, 35, 2210 and references
cited therein. (b) Harvey, H. A.; Lipton, A.; Santin, R. J. Cancer Res. (suppl.) 1982, 42, 3261.
1
6. Selected spectral data of 7: H NMR (300 MHz, CDCl3): l 7.52 (d, J=8.1 Hz, 2H), 7.25–7.32 (m, 7H), 5.03 (d,
J=13.8 Hz, 1H), 4.86 (d, J=13.8 Hz, 1H), 4.05–4.07 (m, 1H), 3.20–3.38 (m, 1H), 2.68–2.82 (m, 2H), 2.43 (s, 3H),
2.20–2.40 (m, 1H).
1
Selected spectral data of 15: H NMR (300 MHz, CDCl3): l 7.56 (d, J=7.8 Hz, 2H), 7.37 (d, J=4.5 Hz, 2H),
7.26–7.32 (m, 5H), 7.19 (s, 1H), 6.20 (s, 1H), 6.01 (d, J=2.7 Hz, 1H), 5.07 (d, J=14.4 Hz, 1H), 4.90 (d, J=14.4
Hz, 1H), 4.34–4.38 (m, 2H), 3.69 (dd, J=6.3, 18.0 Hz, 1H), 3.09 (d, J=18.0 Hz, 1H), 2.45 (s, 3H).
Selected spectral data of 19: 1H NMR (300 MHz, CDCl3): l 7.86 (d, J=8.1 Hz, 4/9H), 7.55 (d, J=8.4 Hz, 14/9H),
7.11–7.39 (m, 12H), 5.07 (d, J=13.8 Hz, 1H), 4.95 (d, J=13.8 Hz, 1H), 4.90 (d, J=2.7 Hz, 2/9H), 4.51 (dd,

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J=5.7, 12.3 Hz, 7/9H), 4.35 (dd, J=5.7, 12.3 Hz, 2/9H), 4.14 (dd, J=3.3, 5.7 Hz, 7/9H), 3.68 (dd, J=3.3, 5.7 Hz,
2/9H), 3.02 (ddd, J=3.3, 5.7, 15.0 Hz, 7/9H), 2.75–2.82 (m, 2/9H), 2.52–2.61 (m, 7/9H), 2.43 (s, 3H).
1
Selected spectral data of 22: H NMR (500 MHz, CDCl3): l 7.79 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H),
7.21–7.26 (m, 8H), 6.93 (dd, J=2.0, 5.0 Hz, 2H), 4.97 (d, J=13.5 Hz, 1H), 4.88 (d, J=13.5 Hz, 1H), 4.04 (dd,
J=5.0, 14.0 Hz, 1H), 3.05 (dd, J=5.0, 14.0 Hz, 1H), 2.59 (t, J=14.0 Hz, 1H), 2.44 (s, 3H), 2.06 (qd, J=6.5, 13.0
Hz, 1H), 1.91 (qd, J=6.5, 13.0 Hz, 1H), 0.86 (t, J=6.5 Hz, 3H).
1
Selected spectral data of 23: H NMR (500 MHz, CDCl3): l 7.35 (d, J=7.5 Hz, 2H), 7.23–7.34 (m, 6H), 7.04 (d,
J=6.0 Hz, 2H), 5.10 (d, J=13.5 Hz, 1H), 4.96 (d, J=13.5 Hz, 1H), 2.68 (d, J=18.0 Hz, 1H), 2.43–2.51 (m, 1H),
2.30–2.33 (m, 1H), 2.17–2.23 (m, 1H), 2.05 (qd, J=6.0, 12.0 Hz, 1H), 1.88 (qd, J=6.0, 12.0 Hz, 1H), 0.84 (t,
J=6.0 Hz, 3H).
Selected spectral data of 24: 1H NMR (500 MHz, CDCl3): l 7.85 (br s, 1H), 7.36–7.39 (m, 2H), 7.26–7.31 (m, 3H),
2.59 (dd, J=4.0, 13.5 Hz, 1H), 2.37–2.44 (m, 2H), 2.21–2.27 (m, 1H), 2.08 (qd, J=7.5, 15.0 Hz, 1H), 1.93 (qd,
J=7.5, 15.0 Hz, 1H), 0.88 (t, J=7.5 Hz, 3H).
.