Synthesis of N-Urethane Protected α-Aminoalkyl-α′-cyanomethyl Ketones; Application to the Synthesis of 3-Substituted 5-Amino-1H-pyrazole Tethered Peptidomimetics

Abstract

The preparation of N-protected amino/peptide α-cyanomethyl ketones through cyanation of the corresponding α-bromomethyl ketones is described. The utility of the resulting α-cyanomethyl ketones in the synthesis of 3-substituted-5-amino-1H-pyrazoles has also been demonstrated. In both steps a wide range of N-protected amino/peptide acids has been employed and the products are obtained in good yield. The enantiomeric purity of both the α-cyanomethyl ketones and pyrazoles were confirmed by chiral HPLC analysis of the corresponding Z-protected d- and l-Ala-OH as model substrates. The synthesis of peptide pyrazolecarboxamides is also delineated.

Key words

peptidomimetics - amino acid mimics - ketones - pyrazole

• References and Notes

• 1a Rijkers DT. S, Van Esse GW, Merkx R, Brouwer AJ, Jacobs HJ. F, Pieters RJ, Liskamp RM. J. Chem. Commun. 2005; 4581
• 1b Sureshbabu VV, Shankar AN, Hemantha HP, Narendra N, Ushati D, Guru Row TN. J. Org. Chem. 2009; 74: 5260
• 2a Ugi I. Isonitrile Chemistry . Academic Press; New York/London: 1971
• 2b Zhu J, Wu X, Danishefsky SJ. Tetrahedron Lett. 2009; 50: 577
• 2c Sureshbabu VV, Narendra N, Nagendra G. J. Org. Chem. 2009; 74: 153
• 3a Sureshbabu VV, Venkataramanarao R, Shankar AN, Chennakrishnareddy G. Tetrahedron Lett. 2007; 48: 7038
• 3b Demko ZP, Sharpless KB. Org. Lett. 2002; 4: 2525
• 4 Tam A, Arnold U, Soellner MB, Raines RT. J. Am. Chem. Soc. 2007; 129: 12670
• 5a Angell YL, Burgess K. Chem. Soc. Rev. 2007; 36: 1674
• 5b Huisgen R. 1,3-Dipolar Cycloaddition-Introduction, Survey, Mechanism. In 1,3-Dipolar Cycloaddition Chemistry. Padwa A. Wiley; New York: 1984: 1-176
• 5c Falorni M, Giacomelli G, Spanu E. Tetrahedron Lett. 1998; 39: 9241
• 6a Domling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3169
• 6b Domling A. Chem. Rev. 2006; 106: 17
• 7a Maareseveen JH. V, Horne WS, Ghadiri MR. Org. Lett. 2005; 7: 4503
• 7b Pedersen DS, Abell A. Eur. J. Org. Chem. 2011; 2399
• 8a Abell AD. Lett. Pept. Sci. 2002; 8: 267
• 8b Spatola AF In Chemistry and Biochemistry of Amino Acids, Peptides and Proteins . Vol. 7. Weinstein B. Dekker; New York: 1983: 267
• 9a Reeder MR, Anderson RM. Chem. Rev. 2006; 106: 2828
• 9b Birch PL, El-Obeid HA, Akthar M. Arch. Biochem. Biophys. 1972; 148: 447
• 9c Albek A, Persky R. Tetrahedron 1994; 50: 6333
• 10 Uekun FM, Perrey DA, Narla RK. Bioorg. Med. Chem. Lett. 2000; 10: 547
• 11a Beaulieu PL, Wernic D, Duceppe J.-S, Guindon Y. Tetrahedron Lett. 1995; 36: 3317
• 11b Onishi T, Hirose N, Nakano T, Nakazawa M, Izawa K. Tetrahedron Lett. 2001; 42: 5883
• 12a Izawa K, Onishi T. Chem. Rev. 2006; 106: 2811
• 12b Beaulieu PL, Lavallee A, Abraham A, Anderson PC, Boucher C, Bousquet Y, Duceppe J.-S, Gillard J, Gorys V, Grand-Maitre C, Grenier L, Guindon Y, Guse I, Plamondon L, Soucy F, Valois S, Wernic D, Yoakim C. J. Org. Chem. 1997; 62: 3440
• 12c Goodman M, Felix A, Moroder L, Toniolo C. Houben-Weyl: Synthesis of Peptides & Peptidomimetics . Vol. E22c. Georg Thieme Verlag; Stuttgart: 2003: 393-395
• 13 Narendra N, Vishwanatha TM, Sudarshan NS, Sureshbabu VV. Protein Pept. Lett. 2009; 16: 1029
• 14 Lalithamba HS, Narendra N, Shankar AN, Sureshbabu VV. ARKIVOC 2010; (xi): 77
• 15a Narendra N, Vishwanatha TM, Sureshbabu VV. Int. J. Pept. Res. Ther. 2010; 16: 283
• 15b Rotella DP. Tetrahedron Lett. 1995; 36: 5453
• 16a Bazewicz CG, Lipkin JS, Lozinak KA, Watson MD, Brewer SH. Tetrahedron Lett. 2011; 52: 6865
• 16b Rappaport Z. The Chemistry of the Cyano Group . Interscience Publishers; London, England: 1970
• 17a Jones G. Org. React. 1967; 15: 204
• 17b Robichaud BA, Liu KG. Tetrahedron Lett. 2011; 52: 6935
• 18 Huff JR. J. Med. Chem. 1991; 34: 2305
• 19 Sauve G, Mansour TS, Lachance P, Belleau B. Tetrahedron Lett. 1988; 29: 2295
• 20a Brillon D, Sauve G. J. Org. Chem. 1992; 57: 1838
• 20b Sauve G, Le Berre N, Zacharie B. J. Org. Chem. 1990; 55: 3002
• 21 Stuk TL, Haight AR, Scarpetti D, Allen MS, Menzia JA, Robbins TA, Parekh SI, Langridge DC, Tien JH. J, Pariza RJ, Kerdesky FA. J. J. Org. Chem. 1994; 59: 4040
• 22 Santos F, Sanchez-Rosello M, Pablo B, Simon-Fuentes A. Chem. Rev. 2011; 111: 6984
• 23 Chen C, Wilcoxen KM, Huang CQ, Xie YF, McCarthy JR, Webb TR, Zhu YF, Saunders J, Liu XJ, Chen TK, Bozigian H, Grigoriadis DE. J. Med. Chem. 2004; 47: 4787
• 24 Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S, Graneto MJ, Lee LF, Malecha JW, Miyashiro JM, Rogers RS, Rogier DJ, Yu SS, Anderson GD, Burton EG, Cogburn JN, Gregory SA, Koboldt CM, Perkins WE, Seibert K, Veenhuizen AW, Zhang YY, Isakson PC. J. Med. Chem. 1997; 40: 1347
• 25 Fancelli D, Berta D, Bindi S, Cameron A, Capella P, Carpinelli P, Catana C, Forte B, Giordano P, Giorgini ML, Mantegani S, Marsiglio A, Meroni M, Moll J, Pittala V, Roletto F, Severino D, Soncini C, Storici P, Tonani R, Varasi M, Vulpetti A, Vianello P. J. Med. Chem. 2005; 48: 3080
• 26 De Luca L, Falorni M, Giacomelli G, Porcheddu A. Tetrahedron Lett. 1999; 40: 8701
• 27 Bagley MC, Davis T, Dix MC, Murziani PG. S, Rokicki MJ, Kipling D. Bioorg. Med. Chem. Lett. 2008; 18: 3745
• 28 Preparation of Boc-Protected Bromomethyl Ketones; Typical Procedure for 2a: To a solution of diazomethyl ketone (1.8 mmol, 0.4 g) in THF, aq 47% HBr (2–3 mL) at 0 °C was added. The reaction mixture was stirred for another 2–3 min until the starting material was completely consumed. The reaction mixture was diluted with excess H₂O and the precipitated solid was filtered. A simple recrystallization (THF–H₂O) led to the analytically pure product
• 29 Preparation of Boc-Ala-[CH₂CN] 3a; Typical Procedure: To a solution of Boc-Ala-CH₂Br (1.8 mmol, 0.5 g) in MeOH (5 mL), KCN (3.7 mmol, 0.24 g) was added at r.t. The reaction mixture was stirred for 3 h (reaction followed by TLC analysis). After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc (2 × 10 mL) and, to dispose of any excess KCN, the reaction mixture was quenched with sat. KMnO₄ solution and washed with excess H₂O. The organic layer was washed with brine (10 mL) and the solution was dried over anhydrous Na₂SO₄. The solvent was filtered and evaporated under reduced pressure and the product 3a was isolated by column chromatography Compound 3a: Yield: 89%; brownish gum; [α]_D ²⁵ –14.2 (c 1.0, CHCl₃); R_f = 0.4 (EtOAc–hexane, 3:7); IR (neat): 1650, 1745, 2243 cm^–1; ¹H MR (CDCl₃, 400 MHz): δ = 1.31 (d, J = 6.0 Hz, 3 H), 1.35 (s, 9 H), 3.19 (s, 2 H), 4.23 (m, 1 H), 6.8 (br, 1 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 13.6, 28.0, 28.7, 56.4, 80.1, 116.5, 155.4, 205.4; HRMS: m/z [M + Na]⁺ calcd for C₁₀H₁₆N₂O₃: 235.1059; found: 235.1062 Compound 3o: Yield: 82%; brownish gum; [α]_D ²⁵ –15.7 (c 1.0, CHCl₃); R_f = 0.4 (EtOAc–hexane, 5:5); IR (neat): 1658, 1718, 1741, 2231 cm^–1; ¹H NMR (CDCl₃, 400 MHz): δ = 0.99 (d, J = 4.8 Hz, 6 H), 1.62 (m, 2 H), 1.78 (m, 1 H), 2.64 (s, 1 H), 3.70 (s, 2 H), 3.78 (m, 2 H), 3.84 (m, 1 H), 4.64 (m, 1 H), 5.12 (m, 2 H), 5.93 (br, 1 H), 7.12 (m, 5 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 22.0, 22.4, 28.4, 40.4, 47.2, 57.3, 63.4, 65.1, 116.2, 127.1, 127.3, 128.3, 140.2, 155.5, 170.8, 207.2; HRMS: m/z [M + Na]⁺ calcd for C₁₉H₂₅N₃O₅: 398.1794; found: 398.1792
• 30 Goodman M, Felix A, Moroder L, Toniolo C. Houben-Weyl: Synthesis of Peptides & Peptidomimetics . Vol. E22c. Georg Thieme Verlag; Stuttgart, New York: 2003: 663-689
• 31 Preparation of Boc-Ala-5-amino-pyrazole 4a; Typical Procedure: To a solution of N ^α-protected Boc-Ala-[CH₂CN] 3a (1.8 mmol, 0.4 g) in MeOH (5 mL), hydrazine hydrate (14 mmol, 0.7 mL) was added. The reaction mixture was heated at reflux at 40 °C for 2 h (progress monitored by TLC). After cooling, the solvent was removed under reduced pressure to obtain the crude product, which was purified by column chromatography (silica gel 100–200 mesh; CHCl₃–MeOH, 9:1). Compound 4a: Yield: 85%; yellowish gum; [α]_D ²⁵ –12.1 (c 1.0, CHCl₃); R_f = 0.3 (CHCl₃–MeOH, 9:1); IR (neat): 1740, 2874, 3429 cm^–1; ¹HNMR (CDCl₃, 400 MHz): δ = 1.34 (d, J = 8.1 Hz, 3 H), 1.40 (s, 9 H), 3.82 (m, 1 H), 5.22 (br, 2 H), 5.80 (s, 1 H), 6.21 (br, 1 H), 9.40 (br, 1 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 19.2, 29.0, 48.3, 80.1, 96.3, 141.2, 155.1, 155.8; HRMS: m/z [M + Na]⁺ calcd for C₁₀H₁₈N₄O₂: 249.1430; found: 249.1427. Compound 4k: Yield: 78%; yellowish gum; [α]_D ²⁵ –20.5 (c 1.0, CHCl₃); R_f = 0.4 (CHCl₃–MeOH, 9:1); IR (neat): 1747, 1762, 2881, 3432 cm^–1; ¹H NMR (CDCl₃, 400 MHz): δ = 0.98 (d, J = 6.3 Hz, 6 H), 1.61–1.63 (m, 2 H), 1.70 (m, 1 H), 2.43–2.54 (s, 1 H), 4.82 (br, 2 H), 5.25 (s, 2 H), 4.50 (t, J = 5.6 Hz, 1 H), 5.34 (s, 2 H), 5.8 (s, 1 H), 6.50 (br, 1 H), 7.11–7.23 (m, 5 H), 10.11 (br, 1 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 19.3, 21.1, 38.9, 49.6, 52.3, 65.1, 65.9, 93.2, 125.7, 127.3, 128.2, 139.9, 142.1, 154.2, 155.8, 169.3; HRMS: m/z [M + Na]⁺ calcd for C₁₉H₂₇N₅O₄: 412.1961; found: 412.1963
• 32 Chiral HPLC details: Agilent 1100 series having G1311A VWD at λ = 230 nm; flow 1.0 mL/min; Column: Phenominex made Lux; pore size 5 μm; Cellusole-1, 250 × 4.6 mm; n-hexane–isopropanol (85:15) in isocratic mode in 40 min
• 33 Dressen D, Garofalo AW, Hawkinson J, Hom D, Jagodzinski J, Marugg JL, Neitzel ML, Pleiss MA, Szoke B, Tung JS, Wone DW. G, Wu J, Zhang H. J. Med. Chem. 2007; 50: 5161
• 34 Černovská K, Kemter M, Gallmeier H.-C, Rzepecki P, Schrader T, König B. Org. Biomol. Chem. 2004; 2: 1603
• 35 Sureshbabu VV, Hemantha HP. ARKIVOC 2008; (ii): 243
• 36 Preparation of Pyrazole-Linked Peptidomimetic 6a; Typical Procedure: To a solution of Fmoc-Val-Cl (0.5 mmol, 0.2 g) and NMM (0.68 mmol, 0.07 mL) in THF at 0 °C, was added Cbz-protected-Ala-5-amino-pyrazole. The reaction mixture was stirred for 2–3 h (TLC monitoring). After completion of reaction, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (10 mL), washed with citric acid (10%, 10 mL), aqueous Na₂CO₃ (10%, 10 mL), H₂O (2 × 10 mL), and brine (2 × 10 mL). The organic phase was dried over anhydrous Na₂SO₄ and then concentrated under reduced pressure. The residue was purification by column chromatography (silica gel 100–200 mesh; CHCl₃–MeOH, 9:1) to afford pyrazolecarboxamides. Compound 6a: Yield: 78%; yellowish solid; [α]_D ²⁵ +52.7 (c 1.0, CHCl₃); R_f = 0.3 (CHCl₃–MeOH, 9:1); IR (neat): 1659, 1766, 2886, 3423 cm^–1; ¹H NMR (CDCl₃, 400 MHz): δ = 0.99 (m, 6 H), 1.30 (d, J = 4.5 Hz, 3 H), 2.01 (m, 1 H), 4.19 (d, J = 3.9 Hz, 1 H), 4.20 (t, J = 6.6 Hz, 1 H), 4.21 (d, J = 7.4 Hz, 2 H), 4.82 (m, 1 H), 5.01 (s, 2 H), 5.18 (m, 2 H), 5.89 (s, 1 H), 6.09 (br, 2 H), 7.25–7.77 (m, 13 H), 11.8 (br, 1 H); ¹³C NMR (CDCl₃, 100 MHz): δ = 16.1, 20.2, 28.0, 42.4, 46.2, 47.5, 52.0, 58.1, 64.9, 66.8, 91.3, 124.6, 125.3, 126.1, 126.8, 127.0, 128.4, 136.1, 139.3, 140.2, 141.6, 143.0, 155.3, 155.5, 170.1; HRMS: m/z [M + Na]⁺ calcd for C₃₃H₃₅N₅O₅: 604.2536; found: 604.2538