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Synlett 2013; 24(5): 591-594
DOI: 10.1055/s-0032-1318316
DOI: 10.1055/s-0032-1318316
letter
A Facile, Inexpensive and Scalable Route to Thiol-Protected α-Methyl Cysteine
Further Information
Publication History
Received: 22 January 2013
Accepted: 06 February 2013
Publication Date:
25 February 2013 (online)
Abstract
A facile, scalable synthesis of α-methyl cysteine with three alternate thiol protecting groups (trityl, allyl and tert-butyl) is described. The thiol-protected amino acids are obtained in six steps from l-cysteine ethyl ester and are ideally suited for a range of natural product and solid-phase peptide synthesis applications.
Key words
natural products - α-methyl cysteine - solid-phase peptide synthesis - camphorsultam auxiliary - P2-EtSupporting Information
- for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett. Included are the preparation of α-methyl cysteine 10, and 1H NMR and 13C NMR spectra for all compounds.
- Supporting Information
-
References and Notes
- 1 Han FS, Osajima H, Cheung M, Tokuyama H, Fukuyama T. Chem. Eur. J. 2007; 13: 3026
- 2 Teruya T, Sasaki H, Fukazawa H, Suenaga K. Org. Lett. 2009; 11: 5062
- 3 Boyce RJ, Mulqueen GC, Pattenden G. Tetrahedron 1995; 51: 7321
- 4 Kicic A, Chua AC. G, Baker E. Br. J. Pharmacol. 2002; 135: 1393
- 5 Boyce RJ, Pattenden G. Tetrahedron 1995; 51: 7313
- 6 Singh S In Recent Research Developments in Organic Chemistry . Vol. 8. Pandalai SG. Transworld Research Network; Kerala, India: 2004: 323
- 7 Ohishi T, Nanba H, Sugawara M, Izumida M, Honda T, Mori K, Yanagisawa S, Ueda M, Nagashima N, Inoue K. Tetrahedron Lett. 2007; 48: 3437
- 8 Fiset D, Charette AB. RSC Advances 2012; 2: 5502
- 9 Kim T.-S, Lee Y.-J, Jeong B.-S, Park H.-G, Jew S.-S. J. Org. Chem. 2006; 71: 8276
- 10 Inoue A, Komeda H, Asano Y. Adv. Synth. Catal. 2005; 347: 1132
- 11 Singh S, Rao SJ, Pennington MW. J. Org. Chem. 2004; 69: 4551
- 12 All traces of the reaction solvent must be removed to obtain maximum yield of product.
- 13 Coste J, Le-Nguyen D, Castro B. Tetrahedron Lett. 1990; 31: 205
- 14 Jin Z, Kim SH, Fuchs PL. Tetrahedron Lett. 1996; 37: 5247
- 15 Lee J, Lee Y.-I, Kang MJ, Lee Y.-J, Jeong B.-S, Lee J.-H, Kim M.-J, Choi J.-Y, Ku J.-M, Park H.-G, Jew S.-S. J. Org. Chem. 2005; 70: 4158
- 16 Liu Y, Liu J, Qi X, Du Y. J. Org. Chem. 2012; 77: 7108
- 17a Bhansali P, Hanigan CL, Casero RA, Tillekeratne LM. V. J. Med. Chem. 2011; 54: 7453
- 17b Matsumoto S, Murao H, Yamaguchi T, Izumida M. U.S. Patent Appl. US 20070010689 A1, 2007
- 18 Almena J, Foubelo F, Yus M. J. Org. Chem. 1996; 61: 1859
- 19 Goudreau N, Brochu C, Cameron DR, Duceppe J.-S, Faucher A.-M, Ferland J.-M, Grand-Maître C, Poirier M, Simoneau B, Tsantrizos YS. J. Org. Chem. 2004; 69: 6185
- 20 Pastuszak JJ, Chimiak A. J. Org. Chem. 1981; 46: 1868
- 21 (2R)-2-Amino-2-methyl-3-[(triphenylmethyl)sulfan-yl]propanoic Acid Phosphate Salt 11 H3PO4 (0.2 mL; 85% aq) was added to a stirred solution of α-methyl cysteine hydrochloride 10 (100 mg, 0.58 mmol) and trityl alcohol (0.15 g, 0.58 mmol) in toluene (5 mL) at r.t. The reaction mixture was heated at reflux for 1 h, cooled to r.t. and then the reaction mixture was concentrated in vacuo. H2O (5 mL) was added and the crude product was stirred for a further 30 min, then filtered and recrystallised from MeOH to give the desired product 11a as a colourless solid (202 mg, 92%); Rf 0.21 (MeOH–CH2Cl2, 1:9); [α]D +30.0 (c 1.00, MeOH); mp 178–180 °C [lit.11 mp 179–180 ºC]. IR (neat): 3471 (NH), 2580–3600 (OH), 1730 (C=O), 1630 (Ar), 1593 (Ar), 1512 (Ar) cm–1. 1H NMR (500 MHz, DMSO): δ = 7.24–7.38 (m, 15 H, ArH), 3.50 (br s, 2 H, NH2), 2.45 (d, J = 11.7 Hz, 1 H, CH ACHB), 2.39 (d, J = 11.7 Hz, 1 H, CHACH B), 1.22 (s, 3 H, CCH3). 13C NMR (126 MHz, DMSO): δ = 171.12 (C), 143.96 (3 × C), 129.08 (6 × CH), 128.11 (6 × CH), 126.88 (3 × CH), 65.99 (C), 58.67 (CH2), 21.96 (CH3), trityl C absent. MS (ESI+, MeOH): m/z (%) = 378 (24) [M + H]+, 243 (100), 179 (10). 1H NMR and 13C NMR spectroscopic data were in good agreement with the literature. (2R)-2-Amino-2-methyl-3-[(prop-2-en-1-yl)sulfanyl]-propanoic Acid 27 Allyl bromide (0.08 mL, 0.87 mmol) was added to a stirred solution of α-methyl cysteine hydrochloride 10 (100 mg, 0.58 mmol) in NH4OH (2 mL, 2 M aq) at r.t. The reaction mixture was stirred at r.t. for 18 h then the product was concentrated in vacuo. The crude product was then recrystallised from EtOH to give the desired product 11b as a colourless solid (79.6 mg, 78%); Rf 0.45 (MeOH–CH2Cl2, 1:9); [α]D +25.0 (c 0.40, H2O); mp 257–259 °C [lit.23 mp 260 °C]. IR (neat): 3454 (NH), 3419 (NH), 2700–3230 (OH), 1738 (C=O), 1605 (C=C), 1597 (COO–) cm–1. 1H NMR (400 MHz, D2O): δ = 5.69–5.83 (m, 1 H, CH=CH2), 5.08–5.20 (m, 2 H, CH=CH 2), 3.08–3.22 (m, 2 H, CH2), 3.05 (d, J = 14.5 Hz, 1 H, CH ACHB), 2.71 (d, J = 14.5 Hz, 1 H, CHACH B), 1.45 (s, 3 H, CCH3). 13C NMR (126 MHz, D2O): δ = 175.30 (C), 133.72 (CH), 118.33 (CH2), 61.14 (C), 36.85 (CH2), 34.94 (CH2), 22.20 (CH3). MS (ESI+, MeOH–CH2Cl2): m/z (%) = 176 (29) [M + H]+, 159 (25), 144 (24), 136 (30), 114 (27), 110 (40). IR data were in good agreement with literature. (2R)-2-Amino-3-(tert-butylsulfanyl)-2-methylpropanoic Acid Hydrochloride Salt 17b HCl (2.5 mL; 37% aq) was added to a stirred solution of α-methyl cysteine hydrochloride 10 (100 mg, 0.58 mmol) in t-BuOH (0.56 g, 5.8 mmol) at r.t. The reaction mixture was heated to 50 °C and stirred for ca. 18 h at the same temperature. Once the reaction was judged to be complete, the reaction mixture was concentrated in vacuo until most of the solvent had been removed. On standing overnight at r.t. colourless crystals formed. The crystals were collected by filtration to give the desired product 11c as a colourless solid (90.3 mg, 81%); Rf 0.10 (MeOH–CH2Cl2, 1:9); [α]D –50.0 (c 0.40, H2O); mp 272–274 °C [lit.17b mp 272–275 °C]. IR (neat): 3389 (NH), 3333 (NH), 2750–3100 (OH), 1734 (C=O) cm–1. 1H NMR (500 MHz, D2O): δ = 3.13 (d, J = 13.4 Hz, 1 H, CH AHBS), 2.93 (d, J = 13.4 Hz, 1 H, CHA H BS), 1.56 (s, 3 H, CCH3), 1.26 [s, 9 H, C(CH3)3]. 13C NMR (126 MHz, D2O): δ = 173.31 (C), 60.07 (C), 43.51 (C), 34.09 (CH2), 29.74 (3 × CH3), 21.79 (CH3). MS (ESI+, MeOH–CH2Cl2): m/z (%) = 192 (58) [M + H]+, 137 (72), 136 (100), 119 (88), 101 (81), 90 (72). 1H NMR and 13C NMR spectroscopic data were in good agreement with the literature.
- 22a Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, Wagner G, Verdine GL, Korsmeyer SJ. Science 2004; 305: 1466
- 22b Baek S, Kutchukian PS, Verdine GL, Huber R, Holak TA, Lee KW, Popowicz GM. J. Am. Chem. Soc. 2012; 134: 103
- 23a Hanessian S, Yang G, Rondeau J.-M, Neumann U, Betschart C, Tintelnot-Blomley M. J. Med. Chem. 2006; 49: 4544
- 23b Besada P, Mamedova L, Thomas CJ, Costanzia S, Jacobson KA. Org. Biomol. Chem. 2005; 3: 2016
- 24a Chalker JM, Bernardes GJ. L, Davis BG. Acc. Chem. Res. 2011; 44: 730
- 24b Chen Y.-X, Triola G, Waldmann H. Acc. Chem. Res. 2011; 44: 762
- 25a Alam J, Keller TH, Loh T.-P. J. Am. Chem. Soc. 2010; 132: 9546
- 25b Hunter L, Condie GC, Harding MM. Tetrahedron Lett. 2010; 51: 5064
- 26 Fiore M, Lo Conte M, Pacifico S, Marra A, Dondoni A. Tetrahedron Lett. 2011; 52: 444
- 27 Nishimura H, Tahara S, Okuyama H, Mitzutani J. Tetrahedron 1972; 28: 4503
For selected examples of RCM peptide stapling with the α-methyl all-carbon homologue, see:
For examples of Grubbs II catalysed RCM macrocyclisation using S-allyl cysteine derivatives, see: