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

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

References and Notes

• 1 Penning TD. Askonas LJ. Djuric SW. Haack RA. Yu SS. Michener ML. Krivi GG. Pyla EY. Bioorg. Med. Chem.  1995,  5:  2517 
• 2a Pedras MSC. Zheng Q.-N. Sarwar MG. Org. Biomol. Chem.  2007,  5:  1167 
• 2b Skey J. O’Reilly RK. Chem. Commun.  2008,  4183 
• 3 Ocain TD. Rich DH. Biochem. Biophys.  1987,  145:  1038 
• 4 Park JD. Kim DH. J. Med. Chem.  2002,  45:  911 
• 5 Hesek D. Toth M. Krchnak V. Fridman R. Mobashery S. J. Org. Chem.  2006,  71:  161 
• 6 Salvador LA. Elofsson M. Kihlberg J. Tetrahedron  1995,  51:  5643 
• 7a Shalaby MA. Grote CW. Rapoport H. J. Org. Chem.  1996,  61:  9045 
• 7b Yamashiro D. Li CH. Int. J. Pept. Protein Res.  1988,  31:  322 
• 8a Spatola AF. Edwards JV. Biopolymers  1986,  25:  229 
• 8b Spatola AF. Bettag AL. J. Org. Chem.  1981,  46:  2393 
• 9 Bienvenue DL. Bennett B. Holz RC. J. Inorg. Biochem.  2000,  78:  43 
• 10 Wynne JH. Jensen SD. Snow AW. J. Org. Chem.  2003,  68:  3733 
• 11 Dehmel F. Weinbrenner S. Julius H. Ciossek T. Maier T. Stengel T. Fettis K. Burkhardt C. Wieland H. Beckers T. J. Med. Chem.  2008,  51:  3985 
• 12 Hu L. Zhu H. Du-Ming D. Xu J. J. Org. Chem.  2007,  72:  4543 
• 13 Wipf P. Jayasuriya N. Chirality  2008,  20:  425 
• 14 Choi J. Yoon NM. Synth. Commun.  1995,  25:  2655 
• 15 Ellis LM. Reid EE. J. Am. Chem. Soc.  1932,  54:  1674 
• 16 Snow SW. Foos EE. Synthesis  2003,  509 
• 17 Choi J. Yoon NM. Synthesis  1995,  373 
• 18 Myllymaki VT. Lindvall MK. Koskinen AMP. Tetrahedron  2001,  57:  4629 
• 19 Tseng S.-L. Yang T.-K. Tetrahedron: Asymmetry  2005,  16:  773 
• 20 Mercey G. Bregeon D. Gaumont A.-C. Levillain J. Gulea M. Tetrahedron Lett.  2008,  49:  6553 
• 21 Meinzer A. Breckel A. Thaher BA. Manicone N. Otto H.-H. Helv. Chim. Acta  2004,  87:  90 
• 22 Xu JX. Chin. J. Org. Chem.  2003,  23:  1 
• 23 Huxtable RJ. Physiol. Rev.  1992,  72:  101 
• 24 Wickberg B. Acta Chem. Scand.  1957,  11:  506 
• 25a Lowik DWPM. Liskamp RMJ. Eur. J. Org. Chem.  2000,  1219 
• 25b de Bont DBA. Moree WJ. Liskamp RMJ. Bioorg. Med. Chem.  1996,  4:  667 
• 25c de Jong R. Rijkers DTS. Liskamp RMJ. Helv. Chim. Acta  2002,  85:  4230 
• 26 Carpino LA. Acc. Chem. Res.  1987,  20:  401 
• 27a Rodriguez M. Llinares M. Doulut S. Heitz A. Maranez J. Tetrahedron Lett.  1991,  32:  923 
• 27b Kokotos G. Noula C. J. Org. Chem.  1996,  61:  6994 
• 28a Mondal S. Fan E. Synlett  2006,  306 
• 28b Caputo R. Cassano E. Longobardo L. Palumbo G. Tetrahedron  1995,  51:  12337 
• 29 Liane S.-U. Racero JC. Antonio JM.-S. Rosario S.-G. James RH. Maykel P.-G. Collado IG. J. Agric. Food Chem.  2009,  57:  2420 
• 30 Gamblin DP. Granier P. van Kasteren S. Oldham NJ. Fairbanks AJ. Davis BJ. Angew. Chem. Int. Ed.  2006,  45:  4007 
• 31 Monnee MCF. Marijne MF. Brouwer AJ. Liskamp RMJ. Tetrahedron Lett.  2000,  41:  7991 
• 32a Higashiura H. Morino H. Matsuura H. Toyomaki Y. Ienaga K. J. Chem. Soc., Perkin Trans. 1  1989,  1479 
• 32b Braghiroli D. Di Bella M. Tetrahedron: Asymmetry  1996,  7:  2745 
• 33 Higashiura K. Lenaga K. J. Org. Chem.  1992,  57:  764 
• 34 Gude M. Piarulli U. Potenza D. Salom B. Gennari C. Tetrahedron Lett.  1996,  37:  8589 
• 35 Brouwer A. Monnee MCF. Liskamp RMJ. Synthesis  2000,  1579 
• 36a Lowik DWPM. Liskamp RMJ. Eur. J. Org. Chem.  2000,  1219 
• 36b Moree WJ. van der Marcel GA. Liskamp RMJ. J. Org. Chem.  1995,  60:  5157 
• 36c Lowik DWPM. Mulders SJE. Cheng Y. Shao Y. Liskamp RMJ. Tetrahedron Lett.  1996,  37:  8253 ; see also ref. 31
• 37a Wang B. Zhang W. Zhang L. Du D.-M. Liu G. Xu J. Eur. J. Org.  2008,  350 
• 37b Xu J. Tetrahedron: Asymmetry  2002,  13:  1129 
• 37c Xu J. Synthesis  2004,  276 
• 37d Xu J. Xu S. Zhang Q. Heteroat. Chem.  2005,  16:  466 
• 38 Hu L. Zhu H. Du D.-M. Xu J. J. Org. Chem.  2007,  72:  4543 
• 39a Gennari C. Solam B. Potenza D. Williams A. Angew. Chem. Int. Ed. Engl.  1994,  33:  2067 
• 39b de Bont DBA. Dijkstra DH. den Hratog JAJ. Liskamp RMJ. Bioorg. Med. Chem. Lett.  1996,  24:  3035 

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 CH₂Cl_{2 (}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.