Synlett 2012; 23(13): 1913-1918
DOI: 10.1055/s-0032-1316586
letter
© Georg Thieme Verlag Stuttgart · New York

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

M. K. Sharnabai
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560 001, India
,
G. Nagendra
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560 001, India
,
Vommina V. Sureshbabu*
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560 001, India
› Author Affiliations
Further Information

Publication History

Received: 05 April 2012

Accepted after revision: 08 June 2012

Publication Date:
23 July 2012 (online)


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.

 
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  • 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); Rf = 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); Rf = 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
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  • 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); Rf = 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); Rf = 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
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  • 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); Rf = 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