Solid phase synthesis of sulfahydantoins

Article abstract of DOI:10.1016/S0040-4039(00)00321-X

A five step solid phase synthesis of 2-unsubstituted 1,2,5- thiadiazolidin-3-one 1,1-dioxides (sulfahydantoins) from N(α)-FMOC-amino acids and aromatic aldehydes is described. The key step is the base mediated cyclitive cleavage of a resin bound N(α)-(aminosulfonyl)-N(α)-benzyl-amino acid to afford the desired product. This synthesis allows the preparation of a diverse library of compounds based on this heterocycle. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00321-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3161–3163
Solid phase synthesis of sulfahydantoins
Fernando Albericio,a,∗ Javier Garcia,a,b Enrique L. Michelotti,b,∗ Ernesto Nicolás a and
Colin M. Tice b,∗
aDepartment of Organic Chemistry, University of Barcelona, 08028- Barcelona, Spain
bRohm and Haas Company, 727 Norristown Road, Spring House, PA 19477-0904, USA
Received 17 December 1999; accepted 21 February 2000
Abstract
A five step solid phase synthesis of 2-unsubstituted 1,2,5-thiadiazolidin-3-one 1,1-dioxides (sulfahydantoins)
from Nα-FMOC-amino acids and aromatic aldehydes is described. The key step is the base mediated cyclitive
cleavage of a resin bound Nα-(aminosulfonyl)-Nα-benzyl-amino acid to afford the desired product. This synthesis
allows the preparation of a diverse library of compounds based on this heterocycle. © 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: amino acids; combinatorial chemistry; cyclitive cleavage; libraries; thiadiazoles.
The first example of the 1,2,5-thiadiazolidin-3-one 1,1-dioxide (‘sulfahydantoin’, 1) ring system
was reported in the literature by Vorreither and Ziegler in 1965.1 Subsequently several groups have
reported syntheses of compounds containing this heterocycle.2 In recent years sulfahydantoins have
been extensively investigated as inhibitors of serine proteases with potential therapeutic application
against diseases such as emphysema and rheumatoid arthritis mediated by these enzymes.3 In addition
sulfahydantoins have been investigated as antihypertensives,4 artificial sweeteners,2f and histamine H2-
receptor antagonists.5
In the course of our efforts to apply solid phase methods to the production of libraries of compounds for
the discovery of novel crop protection agents, we became interested in the sulfahydantoins. By analogy
with the artificial sweetener saccharin (2), we anticipated that N-2-unsubstituted sulfahydantoins (1a)
would be weakly acidic with pKas in the same range as carboxylic acids.6 Weakly acidic compounds
∗
Corresponding authors.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00321-X
tetl 16601

3162
are often phloem-mobile in plants and crop protection agents with this property (‘systemicity’) are
particularly desirable.7
The solid phase synthesis of sulfahydantoins is shown in Scheme 1. The chemistry was developed
on a Wang-resin (Polymer Labs, 1.7 mmol/g) and on an MBHA-resin (Novabiochem, 1.2 mmol/g)
to which the p-alkoxybenzyl alcohol (AB) linker was anchored. FMOC protected phenylalanine was
coupled to the resin under standard conditions using DIC and DMAP in a mixture of CH2Cl2 and DMF
(2 cycles) to give 3a (R1=PhCH2, R2=H). The FMOC group was removed using 20% piperidine in
DMF to afford 4a. Reductive alkylation of the resin bound phenylalanine with 4-methoxybenzaldehyde
was accomplished following the procedure of Szardenings et al. to give 5a.8 Sulfamoyl chloride was
prepared from formic acid and chlorosulfonyl isocyanate2a,2c,9 and immediately reacted with 5a in the
presence of 2,4,6-collidine to afford the resin bound sulfamide intermediate 6a. An alternative procedure
in which 5a was reacted with sulfamide required temperatures >150°C and was not pursued.10 Treatment
of the substituted sulfamide 6a with base was expected to afford the desired product 7a by a cyclitive
cleavage.11 Initial attempts to effect this reaction using sodium methoxide in methanol and THF gave
unsatisfactory results. Better results were obtained with DBU in CH2Cl2. Treatment of the crude product
with Amberlyst A-15 served to remove DBU and 7a was obtained in 76% purity and 23% yield.
Scheme 1. Solid phase synthesis of sulfahydantoins. (i) FMOC-NHCR1R2CO2H (3 equiv.), DIC (3 equiv.), DMAP (0.3
equiv.), CH2Cl2–DMF (5:1), 2 h, rt; (ii) piperidine–DMF (1:4), 20 min, rt; (iii) R3CH2CHO (11 equiv.), HOAc (2 equiv.),
CH2Cl2–(MeO)3CH (1:1), 5 h, rt then NaCNBH3 (11 equiv.), CH2Cl2–(MeO)3CH (1:1), 3×2 h, rt; (iv) H2NSO2Cl (6 equiv.),
2,4,6-collidine (10 equiv.), CH2Cl2, 4 h, rt; (v) DBU, CH2Cl2, 5 h, rt
This procedure was applied to several amino acids and aromatic aldehydes to give the products shown
in Table 1. The use of Amberlyst A-15 to remove DBU precludes the use of amino acids with basic
side chains and aldehydes with basic functionality. Furthermore when an aliphatic aldehyde was used no
product was obtained. Despite these limitations, a diverse array of sulfahydantoins can be prepared using
this methodology.
In conclusion, we have developed a workable solid phase synthesis of sulfahydantoins which has
allowed the preparation of a library compounds for biological testing.
Acknowledgements
We wish to thank Mark Eisenschmied and Francis Acholla for analytical support.

3163
Table 1
Sulfahydantoins synthesized
References
1. Vorreither, H. K.; Ziegler, E. Monatsh. Chem. 1965, 96, 216–219.
2. (a) Timberlake, J. W.; Ray, W. J.; Stevens, E. D.; Klein, C. L. J. Org. Chem. 1989, 54, 5824–5826. (b) Lee, C.-H.; Korp, J. D.;
Kohn, H. J. Org. Chem. 1989, 54, 3077–3083. (c) Lee, C.-H.; Kohn, H. J. Org. Chem. 1990, 55, 6098–6104. (d) Aouf, N.;
Dewynter, G.; Montero, J. L. Tetrahedron Lett. 1991, 32, 6545–6546. (e) Dewynter, G.; Aouf, N.; Regainia, Z.; Montero, J.
L. Tetrahedron 1996, 52, 993–1004. (f) Muller, G. W.; DuBois, G. E. J. Org. Chem. 1989, 54, 4471–4473. (g) Hanewacker,
G. A.; Mester, Z.; Unterhalt, B. Arch. Pharm. 1993, 326, 497–505.
3. (a) Kuang, R.; Epp, J. B.; Ruan, S.; Yu, H.; Huang, P.; He, S.; Tu, J.; Schechter, N. M.; Turbov, J.; Froelich, C. J.; Groutas, W.
C. J. Am. Chem. Soc. 1999, 121, 8128–8129. (b) Groutas, W. C.; Schechter, N. M.; He, S.; Yu, H.; Huang, P.; Tu, J. Bioorg.
Med. Chem. Lett. 1999, 9, 2199–2204. (c) Groutas, W. C.; Kuang, R.; Ruan, S.; Epp, J. B.; Venkataraman, R.; Truong, T. M.
Bioorg. Med. Chem. 1998, 6, 661–671. (d) Groutas, W. C.; Kuang, R.; Venkataraman, R.; Epp, J. B.; Ruan, S.; Prakash, O.
Biochemistry 1997, 36, 4739–4750 (e) Groutas, W. C.; Kuang, R. WO 9909977 (f) Court, J. J.; Desai, R. C. WO 9616970.
(g) Desai, R. C. WO 9616951. (h) Desai, R. C. WO 9616654. (i) Desai, R. C.; Hlasta, D. J. US 5512576. (j) Court, J. J.;
Desai, R. C.; Hlasta, D. J. US 5494925.
4. Mantegani, S.; Brambilla, E.; Caccia, C.; Chiodini, L.; Ruggieri, D.; Lamberti, E.; Di Salle, E.; Salvati, P. Farmaco 1998,
53, 293–304.
5. Crenshaw, R. R.; Algieri, A. A. US 4394508.
6. (a) Lipinski, C. A.; Fiese, E. F.; Korst, R. J. Quant. Struct.-Act. Relat. 1991, 10, 109–117. (b) Lipinski, C. A. Annu. Rep.
Med. Chem. 1986, 21, 283–291. (c) Lipinski, C. A.; Chenard, B. L. Pestic. Sci. 1990, 29, 227–240.
7. (a) Kleier, D. A. Pestic. Sci. 1994, 42, 1–11. (b) Brudenell, A. J.P.; Baker, D. A.; Grayson, B. T. Plant Growth Regulation
1995, 16, 215–231.
8. Szardenings, A. K.; Burkoth, T. S.; Look, G. C.; Campbell, D. A. J. Org. Chem. 1996, 61, 6720–6722
9. Graf, R. Chem. Ber. 1959, 92, 509–513.
10. Paquin, A. M. Angew. Chem. 1948, 60, 316–320.
11. DeWitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Cody, D. M.R.; Pavia, M. R. Proc. Natl. Acad. Sci. USA
1993, 90, 6909–6913.