Peptidomimetic building blocks for the synthesis of sulfonamide peptoids

Article abstract of DOI:10.1016/S0040-4039(99)02240-6

There is a constant demand for novel building blocks for combinatorial chemistry applications. A one-pot synthesis of a novel class of peptidomimetic building blocks to be used for the preparation of sulfonamide peptoids, is presented here. Furthermore, it is shown that these compounds can be incorporated in a peptide sequence. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02240-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1103–1106
Peptidomimetic building blocks for the synthesis of sulfonamide
peptoids
Jeroen van Ameijde and Rob M. J. Liskamp ∗
Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16,
PO Box 80082, 3508 TB Utrecht, The Netherlands
Received 15 October 1999; accepted 29 November 1999
Abstract
There is a constant demand for novel building blocks for combinatorial chemistry applications. A one-pot
synthesis of a novel class of peptidomimetic building blocks to be used for the preparation of sulfonamide peptoids,
is presented here. Furthermore, it is shown that these compounds can be incorporated in a peptide sequence. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: peptidomimetics; sulfonamides; Michael reaction; combinatorial chemistry.
There is a constant need for new building blocks in order to increase diversity in combinatorial
libraries. Peptidomimetics are particularly interesting, because they can be used to mimic biologically
active peptides.1 A wide variety of peptidomimetic building blocks has been developed in the past: e.g.
peptoids,2 sulfonamides,3 ureapeptidomimetics,4 and hydrazinopeptidomimetics.5
In this communication we present a convenient synthesis of a novel type of peptidomimetic building
block to be used for the preparation of sulfonamide peptoids. The general structure of these compounds is
shown in Fig. 1. As can be seen, these compounds actually mimic beta amino acids, which are currently
receiving considerable interest in the literature.6
Fig. 1. General structure of a sulfonamide peptoid
The synthesis of these compounds was first investigated via an analogous route to the one which we
developed earlier for peptoid peptidomimetics2b,c (Scheme 1, route 1). Therefore, the first step in the
route towards building blocks for sulfonamide peptoids involved refluxing 2-bromoethylsulfonate 1 and
two equivalents of amine 2 in water for 48 h. The formation of product could be monitored on TLC.
Isolation of the substitution product 3 turned out to be very difficult because of the zwitter-ionic nature of
∗
Corresponding author. Tel: (31)30-2537396; fax: (31)30-2536655; e-mail: r.m.j.liskamp@pharm.uu.nl (R. M. J. Liskamp)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02240-6
tetl 16168

1104
this compound. Therefore, it was decided to remove excess amine 2 by extraction into dichloromethane
under basic conditions. The aqueous phase, containing inter alia the substitution product 3, was used
directly in the second step: a standard Fmoc-protection under Schotten–Baumann conditions. As it turned
out to be impossible to extract the resulting Fmoc protected monomer 4 into an organic phase even under
strongly acidic conditions, it was decided to use the crude product in the final step of the synthesis, after
evaporation of the solvent and careful drying. This final step involved the treatment of the sulfonate
4 with a solution of phosgene in toluene, in the presence of N,N-dimethylformamide. The resulting
sulfonyl chloride 5 (a sulfonamide peptoid monomer) could be easily isolated and purified by column
chromatography. The overall yield of this virtually one-pot procedure was ca. 35%.
Scheme 1. Synthesis of sulfonamide peptoid monomers
It was then assumed that the first step in the synthesis could be replaced by a Michael addition of amine
2 to vinylsulfonate 6 (Scheme 1, route 2). The advantage of this procedure is that only one equivalent of
amine 2 could be employed because no hydrogen bromide is formed. Using this procedure the three-step
synthesis of sulfonamide peptoid monomers could be carried out in one pot.† Yields were comparable to
those achieved using the first method, viz. 25–40% (Table 1).
Surprisingly, it was found that the different starting materials (1 and 6) in both routes showed similar
Rf-values on TLC. We therefore suspected that the substitution reaction carried out in the first approach
actually proceeds via an elimination–addition tandem reaction (Scheme 2). This was confirmed by an
NMR experiment: a sample of bromide 1 in D2O decomposed quite rapidly into vinylsulfonate 6.
Scheme 2. Mechanism of substitution of 2-bromoethylsulfonate
The second procedure was employed for the convenient synthesis of a number of sulfonamide peptoid
monomers containing either the Fmoc- or Cbz-protecting group. The synthetic procedure for Cbz-
protected sulfonamide peptoids is identical to that of the Fmoc-protected monomers, except that Cbz–Cl
was used instead of Fmoc–Cl at the amine-protection step. The results of these syntheses are summarized
in Table 1.
†
General procedure: To 4.43 ml (10 mmol) of a 25% solution of vinylsulfonate in water, 10 mmol of amine and water (6
ml) were added. The resulting mixture was refluxed for 48 h. After cooling to room temperature, dioxane (10 ml) was added,
and the pH was adjusted to 8.5. Fmoc–Cl (2.59 g, 10 mmol) was added, and the pH of the reaction mixture was kept at 8–8.5
with 1N NaOH. The solvents were then evaporated, and the crude product was dried in vacuo over P2O5. A 20% solution of
phosgene in toluene (12 ml), dichloromethane (20 ml), and DMF (2.5 ml) were added, and this mixture was stirred at room
temperature for 3 h. After filtration, the solvents were evaporated, and column chromatography (eluent: DCM) afforded the
pure sulfonylchloride.

1105
Table 1
Results of the syntheses of sulfonamide peptoid building blocks
As an illustration of the applicability of these novel peptidomimetic building blocks, it was attempted
to incorporate a sulfonamide peptoid monomer in a small peptide (Scheme 3). First, Cbz-NPhe-
Ψ[CH2SO2Cl] 7 was coupled to Leucine methylester 8 using N-methylmorpholine as a base (73%).
Then, after Cbz deprotection by palladium(0)-catalyzed hydrogenolysis, Boc-protected glycine 10 was
coupled to sulfonamide 9 using PyBrOP.7 This coupling reagent was previously employed successfully
in the synthesis of peptoid peptidomimetics2b,c (54%). It is expected that the yields of these coupling
reactions can be improved using solid phase synthesis, in which excess of starting material is used.
Scheme 3. Incorporation of a sulfonamide peptoid residue in a peptide
In conclusion, a convenient route for the synthesis of interesting novel peptidomimetic building blocks
is presented to be used for the preparation of sulfonamide peptoids. Both Fmoc- and Cbz-protected
monomers are accessible, so these compounds can be used in solution as well as in solid phase synthesis.
The applicability was illustrated by incorporating a sulfonamide peptoid in a small peptide.
References
1. (a) Gante, J. Angew. Chem., Int. Ed. Engl. 1993, 33, 1699. (b) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32,
1244.
2. (a) Simon, R. J.; Kania, R. S.; Zuckermann, R. N.; Huebner, V. D.; Jewell, D. A.; Banvill, S.; Ng, S.; Wang, L.; Rosenberg,
S.; Marlowe, C. K.; Spellmeyer, D. C.; Tan, R.; Frankel, A. D.; Santi, D. V.; Cohen, F. E.; Bartlet, P. A. Proc. Natl. Acad.
Sci. USA 1992, 89, 9367. (b) Kruijtzer, J. A. W.; Liskamp, R. M. J. Tetrahedron Lett. 1995, 36, 6969. (c) Kruijtzer, J. A. W.;
Hofmeijer, L. J. F.; Heerma, W.; Versluis, C.; Liskamp, R. M. J. Chem. Eur. J. 1998, 4, 1570.

1106
3. See, for example: (a) Decicco, C. P.; Seng, J. L.; Kennedy, K. E.; Covington, M. B.; Welch, P. K.; Arner, E. C.; Magolda, R.
L.; Nelson, D. J. Bioorg. Med. Chem. Lett. 1997, 7, 2231. (b) Choy, N.; Choi, H.; Won, H. J.; Kim, C. R.; Yoon, H.; Kim, S.
C.; Lee, T. G.; Koh, J. S. J. Med. Chem. 1997, 7, 2635. (c) Moree, W. J.; van der Marel, G. A.; Liskamp, R. M. J. J. Org. Chem.
1995, 60, 5157. (d) Benedetti, F.; Berti, F.; Colombatti, A.; Ebert, C.; Linda, P.; Tonizzo, F. Chem. Commun. 1996, 1417. (e)
Paik, S.; White, E. H. Tetrahedron 1996, 5303. (f) Gude, M.; Piarulli, U.; Potenza, D.; Salom, B.; Gennari, C. Tetrahedron
Lett. 1996, 47, 8589. (g) De Bont, D. B. A.; Dijkstra, G. D. H.; Den Hartog, J. A. J.; Liskamp, R. M. J. Bioorg. Med. Chem.
Lett. 1996, 6, 3035.
4. (a) Burgess, K.; Linthicum, D. S.; Shin, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 907. (b) Burgess, K.; Ibarzo, J.; Linthicum,
D. S.; Russell, D. H.; Shin, H.; Shitangkoon, A.; Totani, R.; Zhang, A. J. J. Am. Chem. Soc. 1997, 119, 1556.
5. (a) Barré, C.; Le Grel, P.; Robert, A.; Bandy-Flock, M. J. Chem. Soc., Chem. Commun. 1994, 607. (b) Han, H.; Janda, K. D.
J. Am. Chem. Soc. 1996, 118, 2539.
6. (a) Guichard, G.; Abele, S.; Seebach, D. Helv. Chim. Acta. 1998, 81, 187. (b) Seebach, D.; Abele, S.; Gademann, K.;
Guichard, G.; Hintermann, T.; Jaun, B.; Matthews, J. L.; Schreiber, J. V. Helv. Chim. Acta. 1998, 81, 932.
7. Coste, J.; Frerot, E.; Jouin, P.; Castro, B. Tetrahedron Lett. 1991, 32, 1967.