Solid-Phase Synthesis of Sulfamate Peptidomimetics Josep Farrera-Sinfreu, †,§ Fernando Albericio, †,‡ and Miriam Royo* ,§ Combinatorial Chemistry Unit and Institute for Research in Biomedicine, Barcelona Science Park, UniVersity of Barcelona, Josep Samitier 1, 08028-Barcelona, Spain, and Department of Organic Chemistry, UniVersity of Barcelona, Martı ´ i Franque ´ s 1, 08028-Barcelona, Spain ReceiVed January 2, 2007 A synthetic method for the preparation of sulfamate peptidomimetics is described. The methodology allows sulfamoylation in the solid phase using sulfamoyl chloride in DMA, followed by the acylation of the corresponding sulfamoylated product. Following this approach, several derivatives have been prepared starting from distinct alcohol sources, including R-, -, and γ-hydroxyacids and phenols. The presence of protected amino functions on the building blocks opens the possibility of the addition of more diversity. This approach, which is compatible with Fmoc/Boc/Alloc protection, provides a useful and efficient tool for the preparation of new sulfamate peptidomimetics. Introduction Synthetic sulfamide- and sulfamate-based compounds play crucial roles in a broad range of biological processes. For example, a number of sulfamide analogues show therapeutic application as inhibitors of HIV protease, 1,2 such as carbonic anhydrase inhibitors, 3 or as potent and selective  3 -adrenergic receptor agonists. 4 Furthermore, sulfamate derivatives show therapeutic properties as inhibitors of steroid sulfatases 5 and aminoacyl-tRNA synthetases. 6 Sulfamoyl chloride is a common reagent for the prepara- tion of sulfamides and sulfamates in solution, and has been used for the preparation of sulfamides and sulfahydantoins on resin. 7 Although sulfamoylation is a powerful strategy for the construction of many sulfamate and sulfamide analogues, to the best of our knowledge no solid-phase sulfamate synthesis has been described. 8 Because of the difficulty of the reproduction of a large number of solution-phase organic reactions on solid supports, we emphasized the development of a powerful solid-phase sulfamoylation, since its products are key intermediates in some of our laboratory programs. Thus, several sulfamoy- lation protocols first described in solution were evaluated, first using trans-hydroxyproline as the alcohol model. Once sulfamoylation conditions were established, other alcohols including R- and -hydroxy acids and phenols were assayed. Results and Discussion trans-Hydroxyproline was chosen as the alcohol model because it was stable under the sulfamoylation conditions and allowed us to check sulfamate stability with respect to other reactions such as Fmoc- and Alloc-removal or acyla- tion. A convenient protection system of the hydroxyl group was required to avoid on-resin polymerization. Tetrahydro- pyrane (THP) was a useful protecting group, orthogonal to Alloc and Fmoc chemistry and even compatible with that of Boc. 9 Fmoc-Hyp(THP)-OH was coupled to the Rink amide resin (see Scheme 1) using common coupling reagents in a solid-phase peptide synthesis (SPPS), such as N,N- diisopropylcarbodiimide (DIPCDI)/1-hydroxybenzotriazole (HOBt). THP was then removed by treatment of the resin with p-TsOH (5 mg/mL) in DCM/MeOH (19:1), which yielded the free alcohol in a quantitative yield. Sulfamoy- lation was then optimized on the Fmoc-Hyp-Rink amide resin. Several sulfamoylation protocols were tested using sul- famoyl chloride (10 equiv) as a reagent. Given that the sulfamoylation methods of aliphatic alcohols in solution require a strong base such as NaH (5 equiv), this base was assayed in the solid phase using ethyleneglycol dimethyl ether (DME) as a solvent. 10,11 However, this method did not work properly when adapted to the solid phase. Although the desired product was detected by HPLC-MS when the reaction was carried out with a few milligrams (50 mg) of resin, no attempt to optimize the strategy was made because this base was difficult to remove from the resin, even with MeOH and H 2 O washings. This problem was even ag- gravated when the reaction was scaled up to 1 g of resin. Similar problems were obtained when K 2 CO 3 (3 equiv) was used, alone or in the presence of 18-crown-6 (3 equiv) in DCM. The use of weak bases such as NEt 3 (3 equiv) or DIEA (10 equiv) in DMF or DCM was abandoned because sulfamoylation was not achieved, and the starting material was obtained. This phenomenon may arise from the decom- position of sulfamoyl chloride in the presence of a base which can compete with sulfamoylation. 12 Furthermore, the pres- ence of a base can also lead to over-sulfamoylation. The use of other solvents which achieve good swelling of the resin, such as DCM, DMF, or THF without base, did not yield the sulfamoylated compound, even after heating the resin at 50 °C (DMF and THF) or using ultrasound * To whom correspondence should be addressed. E-mail: mroyo@pcb.ub.es. † Combinatorial Chemistry Unit. ‡ Institute for Research in Biomedicine. § Department of Organic Chemistry. 501 J. Comb. Chem. 2007, 9, 501-506 10.1021/cc070002g CCC: $37.00 © 2007 American Chemical Society Published on Web 03/16/2007