Download PDF
Synlett 2010(7): 1037-1042  
DOI: 10.1055/s-0029-1219584
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Simple Synthesis of N β-Fmoc/Z-Amino Alkyl Thiols and their use in the Synthesis of N β-Fmoc/Z-Amino Alkyl Sulfonic Acids

V. V. Sureshbabu*, T. M. Vishwanatha, B. Vasantha
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi, Bangalore University, Bangalore 560001, India
e-Mail: sureshbabuvommina@rediffmail.com; e-Mail: hariccb@hotmail.com;
Further Information

Publication History

Received 10 December 2009
Publication Date:
17 March 2010 (online)

    Permissions and Reprints All articles of this category

Abstract

A simple and efficient protocol for the synthesis of N β-Fmoc/Z-amino alkyl thiols is described. The approach uses sodium pyrosulfite-mediated hydrolysis of isothiouronium salts resulting from the reaction between N-protected aminoalkyl iodides and thiourea. N-Protected taurines were prepared through performic acid oxidation of the thiols and the products were further utilized for the synthesis of dipeptidosulfonamides.

Key words

alkyl iodides - thiourea - alkyl thiols - N-protected taurines - isothiuronium salts

40

General procedure for 2a-l: A solution of N β-Fmoc/Z-amino alkyl iodide 1a-l (1.0 mmol) and thiourea (2.1 g, 3.0 mmol) in anhydrous acetone (10.0 mL) was heated at reflux under an argon atmosphere for 8-10 h. The consumption of the iodide was monitored by TLC. The solvent was evaporated under vacuum and the isothouronium salt was isolated as the pure compound by recrystallization from acetone-diethyl ether.

41

Spectroscopic data for 2d: IR (KBr): 1703, 1657, 3211 cm-¹; ¹H NMR (400 MHz, DMSO-d 6): δ = 0.91 (2 × d, J = 6.1 Hz, 6 H), 1.76-2.08 (m, 1 H), 2.98-3.10 (m, 2 H), 3.96-4.01 (m, 1 H), 4.18 (t, J = 6.9 Hz, 1 H), 4.39 (d, J= 4.9 Hz, 2 H), 5.01 (br, 1 H), 6.94-7.77 (m, 8 H), 9.10 (br, 2 H), 9.32 (br, 2 H); ¹³C NMR (100 MHz, DMSO-d 6): δ = 17.8, 25.4, 30.1, 47.3, 55.2, 66.1, 119.5, 124.8, 125.5, 127.0, 127.9, 141.0, 143.8, 144.2, 156.3, 161.2.

42

General procedure for 3a-l: Isothiouronium salt 2 (1.0 mmol) and sodium pyrosulfite (1.5 mmol) were dissolved in CH2Cl2 (10.0 mL) and H2O (2.0 mL) and heated at reflux under argon atmosphere until completion of reaction. The mixture was diluted with excess CH2Cl2, and the organic extract was washed with H2O (2 × 10 mL) and brine (10 mL), and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel; 100-150 mesh; EtOAc-hexane, 15%).

43

Selected spectroscopic data: 3c: IR (KBr): 1711 cm-¹; ¹H NMR (400 MHz, CDCl3): δ = 2.23 (s, 1 H), 2.81-3.05 (m, 4 H), 3.65 (d, J = 3.5 Hz, 2 H), 3.71-3.97 (m, 1 H), 4.17 (t, J = 6.8 Hz, 1 H), 5.02 (br, 1 H), 6.97-7.67 (m, 13 H); ¹³C NMR (100 MHz, CDCl3): δ = 30.8, 40.3, 47.1, 52.8, 67.4, 120.4, 125.6, 127.0, 127.8, 128.5, 129.3, 137.0, 141.7, 144.5, 155.8. 3j: IR (KBr): 1694 cm-¹; ¹H NMR (400 MHz, CDCl3): δ = 0.85 (t, J = 2.8 Hz, 3 H), 0.96 (d, J= 4.2 Hz, 3 H), 1.12-1.35 (m, 2 H), 2.05 (s, 1 H), 2.32-2.45 (m, 1 H), 2.71 (dd, J = 2.7 Hz, 1 H), 3.01 (dd, J = 3.1 Hz, 1 H), 3.56-3.71 (m, 1 H), 4.90 (br, 1 H), 5.05 (s, 2 H), 7.21 (s, 5 H); ¹³C NMR (100 MHz, CDCl3): δ = 10.5, 13.6, 24.2, 28.6, 39.4, 57.6, 64.8, 127.2, 128.0, 128.8, 137.6, 155.8.

44

General experimental procedure for 4a-l: H2O2 (30%, 15.0 mL) was dissolved in 98% formic acid (35.0 mL) at 0 ˚C and the mixture was stirred at this temperature for 1 h to afford performic acid. Fmoc/Z-amino alkyl thiol in 98% formic acid (3.0 mL) solution was added dropwise to the performic acid solution and the resulting reaction mixture was stirred at r.t. for 1 d. After removal of the solvent, the product was purified by column chromatography (CHCl3-MeOH, 8:1) to afford N-protected taurines as colorless solids.

45

Selected spectroscopic data: 4b: IR (KBr): 1708, 1211, 1118 cm-¹; ¹H NMR (400 MHz, DMSO-d 6): δ = 1.11 (d, J = 6.53 Hz, 3 H), 2.58 (dd, J = 2.9 Hz, 1 H), 2.78 (dd, J = 3.0 Hz, 1 H), 3.25-3.45 (m, 1 H), 4.15 (t, J = 6.8 Hz, 1 H), 4.41 (d, J = 4.8 Hz, 2 H), 6.13 (br, 1 H), 7.02-7.57 (m, 8 H); ¹³C NMR (100 MHz, DMSO-d 6): δ = 17.5, 41.2, 46.8, 57.5, 64.8, 120.1, 125.2, 126.9, 127.8, 141.1, 142.8, 155.03. 4j: IR (KBr): 1691, 1217, 1170 cm-¹; ¹H NMR (400 MHz, DMSO-d 6): δ = 0.76 (t, J = 2.3 Hz, 3 H), 0.98 (d, J = 5.0 Hz, 3 H), 1.31-1.40 (m, 2 H), 2.12-2.31 (m, 1 H), 2.75 (dd, J = 2.5 Hz, 1 H), 3.03 (dd, J = 3.1 Hz, 1 H), 3.57-3.62 (m, 1 H), 4.68 (s, 2 H), 5.92 (br, 1 H), 6.98 (s, 5 H); ¹³C NMR (100 MHz, DMSO-d 6): δ = 0.2, 13.6, 24.6, 37.8, 45.8, 55.3, 64.4, 128.1, 128.8, 137.5, 154.8.

46

General procedure for the synthesis of Fmoc-Xaa-ψ[CH 2 SO 2 Cl](5): To a suspension of 4 (1.0 mmol) in anhydrous CH2Cl2 (10.0 mL) at 0 ˚C, triphosgene (0.7 mmol) and a catalytic amount of DMF were added and the mixture was stirred overnight. The mixture was diluted with CH2Cl2 (10 mL) and the organic layer was washed with H2O (2 × 10 mL) and brine (10 mL), then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (silica gel, 100-150 mesh; EtOAc-hexane, 10%).

47

Spectroscopic data for 5a: Yield 78%; white solid; mp 151 ˚C. IR (KBr): 1708 cm-¹; ¹H NMR (400 MHz, CDCl3): δ = 1.35 (d, J = 6.0 Hz, 3 H), 3.58 (dd, J = 2.8 Hz, 1 H), 3.65 (d, J = 3.5 Hz, 2 H), 3.97-4.08 (m, 1 H), 4.20 (t, J = 6.8 Hz, 1 H), 4.31-4.39 (m, 1 H), 5.11 (br, 1 H), 7.04-7.70 (m, 8 H); ¹³C NMR (100, MHz, CDCl3): δ = 19.3, 44.0, 46.9, 66.8, 69.1, 119.5, 125.6, 127.2, 128.0, 141.2, 143.8, 155.5.

48

General procedure for the synthesis of 6: To an ice-cooled solution of N-Fmoc-Xaa-ψ[CH2SO2Cl] (1.0 mmol) in anhydrous CH2Cl2, was added a solution of amino acid methyl ester in CH2Cl2 (1.0 mmol, obtained by neutralizing the corresponding hydrochloride salt using zinc dust), followed by Et3N (1.0 mmol). The resulting suspension was stirred for 6-8 h. After dilution with excess CH2Cl2 (25 mL), it was washed with 1M HCl (2 × 10 mL), sat. NaHCO3 (2 × 10 mL), and brine (10 mL), dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, 100-150 mesh; EtOAc-hexane, 30%).

49

Selected spectroscopic data: 6a: White solid; mp 163 ˚C. ¹H NMR (400 MHz, DMSO-d 6): δ = 0.98-1.12 (m, 6 H), 1.23 (d, J = 5.9 Hz, 3 H), 2.08-2.15 (m, 1 H), 3.06 (d, J = 4.5 Hz, 1 H), 3.21 (s, 3 H), 3.78 (dd, J = 2.6 Hz, 1 H), 3.98 (t, J = 3.8 Hz, 1 H), 4.01 (dd, J = 3.0 Hz, 1 H), 4.12 (d, J = 5.8 Hz, 2 H), 4.21-4.31 (m, 1 H), 5.06-5.11 (br, 2 H), 7.12-7.69 (m, 8 H); ¹³C NMR (100 MHz, DMSO-d 6): δ = 7.0, 18.2, 30.6, 37.2, 47.3, 50.3, 63.2, 66.7, 120.2, 125.6, 127.3, 127.8, 141.3, 143.6, 154.6, 170.2. 6c: White solid; mp 143 ˚C. ¹H NMR (400 MHz, DMSO-d 6): δ = 1.17 (d, J = 5.4 Hz, 3 H), 3.10 (s, 3 H), 3.59 (dd, J = 2.2 Hz, 1 H), 3.63-3.75 (m, 1 H), 4.04 (s, 1 H), 4.12 (d, J = 5.6 Hz, 2 H), 5.23-5.64 (br, 2 H), 7.12-7.82 (m, 13 H); ¹³C NMR (100 MHz, DMSO-d 6): δ = 18.9, 34.5, 50.6, 54.8, 62.7, 66.1, 47.4, 120.6, 125.1, 127.4, 127.1, 141.0, 143.1, 155.0, 170.1.