Solid-phase synthesis of 1,3-diamino ketones

Aoyagi, T.; Umezawa, H. In Proteases and Biological Control; Reich, E.; Rifkin, D. B.; Shaw, E., Eds.; Cold Spring Harbor Press: Cold Spring Harbor, 1975; pp. 429–454. For a recent review on the synthesis of small molecule inhibitors of cysteine proteases, see: Rasnick, D. Perspect. Drug Discovery Des. 1996, 647. (a) Mehdi, S. Biorg. Chem. 1993, 21, 249. (b) Li, Z.; Patil, G. S.; Golubski, Z. E.; Hori, H.; Tehrani, K.; Foreman, J. E.; Evelth, D. D.; Bartus, R. T.; Powers, J. C. J. Med. Chem. 1993, 36, 3472. (c) Tao, M.; Bihovsky, R.; Kauer, J. C. Biorg. Med. Chem. Lett. 1996, 6, 3009. Yamashita, D. S., et al. J. Am. Chem. Soc. 1997, 119, 11351. (b) LaLonde, J. M., et al. J. Med. Chem. 1998, 41, 4567. While this work was in progress, an alternate method for solid-phase synthesis of 1,3-bis(acylamino)-2-butanones was reported by researchers from SmithKline Beecham Pharmaceuticals and the University of California, Berkley: Yamashita, D. S.; Dong, X.; Oh, H.-J.; Brook, C. S.; Tomaszek, T. A.; Szewczuk, L.; Tew, D. G.; Veber, D. F. J. Comb. Chem. 1999, 1, 207. Lee, A.; Huang, L.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 9907. Also, for an earlier work on the synthesis of diamino alcohol-based aspartic acid protease inhibitors, using a similar approach, see: Keck, E. K.; Ellman, J. A. J. Med. Chem. 1995, 38, 1427. For use of o-nitrobenzene sulfonamide as a protecting group for amines, see: Fukuyama, T.; Jow, C. K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373. Also for use of this protecting group in SPOS, see: Miller, S. C.; Scanlan, T. S. J. Am. Chem. Soc. 1997, 119, 2301. Baker, B. R.; Querry, M. V.; Kadish, A. F. J. Org. Chem. 1950, 15 The polymer-bound THP linker was purchased from Nova Biochem and alcohol 10 was immobilized as described in: Thompson, L. A.; Ellman, J. A. Tetrahedron Lett. 1994, 35, 9333. The loading was determined to be >90% of theory by cleavage of an aliquot of 11 (6:1 TFA: H2O) to provide alcohol 10. General procedure for the synthesis of 1: To a suspension of 2.4 g of resin 11 (0.63 mmol/g, 1.5 mmol) in 3:1 DMF:THF (15 mL) was added hydrazine hydrate (10 mL). After shaking at rt for 16 h, the resin was collected by filtration, washed (DMF, THF, MeOH) and dried. To 0.4 g of the resulting resin (0.25 mmol based on 0.63 mmol/g loading) in 2:1 DCE:DIEA (12 mL) was added 4-phenoxy benzenesulfonyl chloride (1.25 mmol, 5 equiv.). After stirring at rt overnight, the resin was collected by filtration, washed and dried. It was resuspended in NMP (2 mL) and DBU (5 mmol,) and β-mercaptoethanol (3 mmol, 12 equiv.) were added and gently stirred at rt for 20 h. The resin was filtered washed and dried. DMF (4 mL) was added followed by Z-Leu-OH (5 equiv.), HOBt (5 equiv.) and DIC (5 equiv.). The resulting mixture was shaken at rt for 20 h, filtered, washed and dried. To the resulting resin was added 6:1 TFA:H2O (5 mL) and the reaction mixture was stirred for 15 min. The resin was filtered off and washed with CH3CN (5 mL). The combined filtrates were combined and evaporated to dryness in vacuo. The residue was suspended in acetone (5 mL), Jones reagent (1.5 mL) was added and the mixture stirred at rt overnight. i-PrOH (1 mL) was added and the solids filtered off. The filtrate was concentrated in vacuo, dissolved in DCE (5 mL) and satd. NaHCO3 (2 mL) was added. After shaking at rt for 10 min, the biphasic mixture was loaded onto a Chemelut® cartridge, allowed to stand for 5 min and eluted with DCE (10 mL). The combined eluents were concentrated in vacuo and the residue purified by preparative TLC (100% EtOAc) to give 0.04 g (30% of theory) of ketone 1b as a white solid. Parlow, J. J.; Case, B. L.; South, M. S. Tetrahedron 1999, 6785. All compounds were characterized by a combination of 1H NMR, MS and the purity determined by a reverse phase HPLC.