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Synlett 2016; 27(09): 1403-1407
DOI: 10.1055/s-0035-1561568
DOI: 10.1055/s-0035-1561568
letter
Expedient Synthesis of Fmoc-(S)-γ-Fluoroleucine and Late-Stage Fluorination of Peptides
Weitere Informationen
Publikationsverlauf
Received: 12. Oktober 2015
Accepted after revision: 19. Januar 2016
Publikationsdatum:
16. Februar 2016 (online)
![](https://www.thieme-connect.de/media/synlett/201609/lookinside/thumbnails/st-2015-b0809-l_10-1055_s-0035-1561568-1.jpg)
Abstract
A concise synthesis of (S)-γ-fluoroleucine is described in five steps from commercially available compounds, with an overall yield of 57%. The Markovnikov hydrofluorination reaction of the unsaturated amino acid precursor as last step of the synthesis proved to be effective. This fluorination can also be performed directly on a short peptide model with the same efficiency. This reaction could be in principle applicable for the preparation of radiolabeled amino acids and peptides.
Key words
(S)-γ-fluoroleucine - peptides - stereoselective synthesis - Selectfluor - late-stage fluorinationSupporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1561568.
- Supporting Information
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References and Notes
- 1a Carpentier C, Godbout R, Otis F, Voyer N. Tetrahedron Lett. 2015; 56: 1244
- 1b Hunter L, Butler S, Ludbrook SB. Org. Biomol. Chem. 2012; 10: 8911
- 1c Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
- 1d Muller K, Faeh C, Diederich F. Science 2007; 317: 1881
- 2a Zhu R.-Y, Tanaka K, Li G.-C, He J, Fu H.-Y, Li S.-H, Yu J.-Q. J. Am. Chem. Soc. 2015; 137: 7067
- 2b Zhang Q, Yin X.-S, Chen K, Zhang S.-Q, Shi B.-F. J. Am. Chem. Soc. 2015; 137: 8219
- 2c Miao J, Yang K, Kurek M, Ge H. Org. Lett. 2015; 17: 3738
- 2d Wuttke C, Ford R, Lilley M, Grabowska U, Wiktelius D, Jackson RF. W. Synlett 2012; 243
- 2e Kee CW, Chin KF, Wong MW, Tan C.-H. Chem. Commun. 2014; 50: 8211
- 3 Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. J. Med. Chem. 2015; 58: 8315
- 4 Bonetti A, Pellegrino S, Das P, Yuran S, Bucci R, Ferri N, Meneghetti F, Castellano C, Reches M, Gelmi ML. Org. Lett. 2015; 17: 4468
- 5 Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2015; 54: 3216
- 6 Papageorgiou C, Borer X, French RR. Bioorg. Med. Chem. Lett. 1994; 4: 267
- 7 Limanto J, Shafiee A, Devine PN, Upadhyay V, Desmond RA, Foster BR, Gauthier DR, Reamer RA, Volante RP. J. Org. Chem. 2005; 70: 2372
- 8 Truong VL, Gauthier JY, Boyd M, Roy B, Scheigetz J. Synlett 2005; 1279
- 9 Nadeau C, Gosselin F, O’Shea PD, Davies IW, Volante RP. Synlett 2006; 291
- 10 Padmakshan D, Bennett SA, Otting G, Easton CJ. Synlett 2007; 1083
- 11 Fanelli R, Jeanne-Julien L, René A, Martinez J, Cavelier F. Amino Acids 2015; 47: 1107
- 12 Lygo B, Andrews BI. Acc. Chem. Res. 2004; 37: 518
- 13 Barker TJ, Boger DL. J. Am. Chem. Soc. 2012; 134: 13588
- 14 Croft AK, Easton CJ, Radom L. J. Am. Chem. Soc. 2003; 125: 4119
- 15 Gottler LM, Lee H.-Y, Shelburne CE, Ramamoorthy A, Marsh EN. G. ChemBioChem 2008; 9: 370
- 16 Feeney J, McCormick JE, Bauer CJ, Birdsall B, Moody CM, Starkmann BA, Young DW, Francis P, Havlin RH, Arnold WD, Oldfield E. J. Am. Chem. Soc. 1996; 118: 8700
- 17a Fraser SA, Easton CJ. Aust. J. Chem. 2015; 68: 9
- 17b Arthur IN, Hennessy JE, Padmakshan D, Stigers DJ, Lesturgez S, Fraser SA, Liutkus M, Otting G, Oakeshott JG, Easton CJ. Chem. Eur. J. 2013; 19: 6824
- 18a Qiu X.-L, Qing F.-L. Eur. J. Org. Chem. 2011; 3261
- 18b O’Shea PD, Chen C.-y, Gauvreau D, Gosselin F, Hughes G, Nadeau C, Volante RP. J. Org. Chem. 2009; 74: 1605
- 18c Formicola L, Maréchal X, Basse N, Bouvier-Durand M, Bonnet-Delpon D, Milcent T, Reboud-Ravaux M, Ongeri S. Bioorg. Med. Chem. Lett. 2009; 19: 83
- 19a Bouhlel A, Zhou D, Li A, Yuan L, Rich KM, McConathy J. J. Med. Chem. 2015; 58: 3817
- 19b Wang L, Zha Z, Qu W, Qiao H, Lieberman BP, Plössl K, Kung HF. Nucl. Med. Biol. 2012; 39: 933
- 19c Wang L, Qu W, Lieberman BP, Plössl K, Kung HF. Nucl. Med. Biol. 2011; 38: 53
- 20 Fmoc-(S)-γ-fluoroleucine (5) Iron(III) oxalate hexahydrate (319 mg, 0.33 mmol) was stirred in H2O (13.8 mL) until complete dissolution (ca. 2 h). The solution was cooled to 0 °C and degassed for 10 min. Selectfluor (234 mg, 0.66 mmol) and MeCN (6.6 mL) were added to the reaction mixture. A solution of 4 (135 mg, 0.33 mmol) in MeCN (6.6 mL) was transferred into the reaction mixture, and NaBH4 (37.5 mg, 0.99 mmol) was added at 0 °C. After 2 min, the reaction was treated with an additional portion of NaBH4 (37.5 mg, 0.99 mmol). The resulting mixture was stirred for 30 min at 0 °C before being quenched by addition of 28–30% aq NH4OH (6.6 mL). The mixture was extracted with 10% MeOH in CH2Cl2, the organic layer was dried over MgSO4, and concentrated under reduced pressure. Flash chromatography (SiO2, cyclohexane–EtOAc = 95:5) provided 5 as a colorless oil (105 mg, 76%). 1H NMR (300 MHz, CDCl3): δ = 1.32 (d, J = 5.2 Hz, 3 H), 1.35 (s, 3 H), 1,38 (s, 9 H), 1.90–2.08 (m, 2 H), 4.15 (t, J = 7.1 Hz, 1 H), 4.25–4.35 (m, 2 H), 5.35 (br d, J = 7.3 Hz, 1 H), 7.22 (dt, J 1 = 1.2, J 2 = 7.4 Hz, 2 H), 7.31 (t, J = 7.4 Hz, 2 H), 7.52 (d, J = 7.3 Hz, 2 H), 7.70 (d, J = 7.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.4, 155.7, 143.9, 143.8, 141.3, 127.7, 127.0, 125.1, 119.9, 95.0 (J = 166.1 Hz), 82.2, 67.0, 52.0, 47.2, 42.7 (J = 22.1 Hz), 27.9, 27.4 (J = 24.6 Hz), 26.6 (J = 24.6 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –135.7 ppm. ESI-HRMS: m/z C25H30NO4NaF calculated [M + Na]: 450.2053; found: 450.2057. Compound 6 The dipeptide Boc-Ala-Gly-OH was directly coupled to the free amino ester extracted after acidic cleavage of benzophenonimine derivative 3, in DMF, in the presence of BOP (1 equiv) and DIPEA (3 equiv). The mixture was stirred for 24 h at room temperature. The solvent was evaporated, and the residue was diluted with EtOAc and consecutively extracted with 1 M KHSO4 (2×), aq NaHCO3 (2×) and brine (2×), dried over Na2SO4, and the solvent was evaporated under reduced pressure to afford the crude product. Flash chromatography (SiO2, cyclohexane–EtOAc = 20:80) provided 6 as a colorless oil (210 mg, 85%). 1H NMR (300 MHz, CDCl3): δ = 1.35 (d, J = 7.1 Hz, 2 H), 1.41 (s, 9 H), 1.43 (s, 9 H), 1.43 (s, 3 H), 2.36 (dd J 1 = 7.9 Hz, J 2 = 13.9 Hz, 1 H), 2.48 (dd J 1 = 6.1 Hz, J 2 = 13.9 Hz, 1 H), 3.94 (ddd, J 1 = 5.5 Hz, J 2 = 16.6 Hz, J 3 = 34.0 Hz, 2 H), 4.17–4.22 (m, 1 H), 4.55 (q, J = 6.2 Hz, 1 H), 4.72 (s, 1 H), 4.80 (t, J = 1.5 Hz, 2 H), 5.34 (br d, J = 6.9 Hz, 1 H), 6.87 (br d, J = 7.7 Hz, 1 H), 7.16 (br t, J = 5.2 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.4, 171.0, 168.5, 155.5, 140.5, 114.3, 103.3, 82.2, 80.0, 51. 2, 50.2, 42.9, 40.6, 28.3, 27.9, 21.8, 18.4 ppm. ESI-HRMS: m/z calcd for C20H35N3O6Na [M + Na]: 436.2421; found: 436.2424. Compound 7 Following the procedure described for compound 5, peptide 7 was prepared starting from precursor 6 (37 mg, 0.089 mmol) and purified by flash chromatography (SiO2, n-hexane–EtOAc = 30:70) providing the desired compound as a colorless oil (30 mg, 77%). 1H NMR (300 MHz, CDCl3): δ = 1.29 (d, J = 8.9 Hz, 3 H), 1.31 (d, J = 7.0 Hz, 3 H), 1.37 (s, 9 H), 1.37 (s, 9 H), 1.93–2.08 (m, 2 H), 3.90 (ddd, J 1 = 5.6 Hz, J 2 = 16.8 Hz, J 3 = 37.4 Hz, 2 H), 4.06–4.16 (m, 1 H), 4.44–4.51 (m, 1 H), 5.01 (br d, J = 6.8 Hz, 1 H), 6.71 (br d, J = 6.0 Hz, 1 H), 6.82 (br t, J = 5.0 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 173.1, 170.8, 168.3, 155.5, 95.1 (J = 165.9 Hz), 82.2, 80.3, 50.4, 43.0, 42.1 (J = 22.0 Hz), 28.3, 27.8, 27.3 (J = 25.6 Hz), 26.5 (J = 24.5 Hz), 18.2 ppm. 19F NMR (376 MHz, CDCl3): δ = –135.6 ppm. ESI-HRMS: m/z calcd for C20H37N3O6F [M + H]: 434.2666; found: 434.2666. Compound 8 Cbz-l-Asp(OBzl)-OH was directly coupled to the free amine extracted after acid cleavage of benzophenonimine derivative 3 in a solution of the free amino ester in DMF in the presence of HATU (1 equiv) and DIPEA (3 equiv). The mixture was stirred for 24 h at room temperature. The solvent was evaporated, and the residue was diluted with EtOAc and consecutively extracted with 1 M KHSO4 (2×), aq NaHCO3 (2×) and brine (2×), dried over Na2SO4, and the solvent was evaporated under reduced pressure to afford the crude product. Flash chromatography (SiO2, cyclohexane–EtOAc = 80:20) provided 8 as colorless oil (590 mg, 75%). 1H NMR (300 MHz, CDCl3): δ = 1.47 (s, 9 H), 1.76 (s, 3 H), 2.43 (ddd, J 1 = 6.0 Hz, J 2 = 14.0 Hz, J 3 = 52.4 Hz, 2 H), 2.76 (dd, J 1 = 6.4 Hz, J 2 = 17.2 Hz, 1 H), 3.08 (dd, J 1 = 4.1 Hz, J 2 = 17.2 Hz, 1 H), 4.51–4.55 (m, 1 H), 4.63–4.67 (m, 1 H), 4.74 (s, 1 H), 4.83 (s, 1 H), 5.11–5.19 (m, 4 H), 5.95 (br d, J = 8.4 Hz, 1 H), 6.88 (br d, J = 6.7 Hz, 1 H), 7.36–7.39 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.7, 170.6, 169.8, 155.9, 140.6 136.0, 135.3, 128.6, 128.4, 128.3, 128.1, 114.5, 82.1, 67.2, 66.9, 51.3, 50.8, 40.5, 36.2, 27.9, 21.8 ppm. ESI-HRMS: m/z calcd for C29H37N2O7 [M + H]: 525.2603; found: 525.2601. Compound 9 Following the same procedure described for compound 5, peptide 9 was prepared starting from precursor 8 (170 mg, 0.324 mmol) and purified by flash chromatography (SiO2, cyclohexane–EtOAc = 80:20) providing the desired compound as a colorless oil (133 mg, 75%). 1H NMR (300 MHz, CDCl3): δ = 1.36 (d, J = 11.2 Hz, 3 H), 1.41 (d, J = 11.2 Hz, 3 H), 1.44 (s, 9 H), 1.93–2.15 (m, 2 H), 2.74 (dd, J 1 = 6.17 Hz, J 2 = 17.3 Hz, 1 H), 3.10 (dd, J 1 = 3.9, J 2 = 17.1 Hz, 1 H), 4.46–4.51 (m, 1 H), 4.61–4.66 (m, 1 H), 5.08–5.16 (m, 4 H), 5.93 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 6.0 Hz, 1 H), 7.34–7.36 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.7, 170.5, 169.9, 156.0, 136.0, 135.3, 128.6, 128.5, 128.3, 128.3, 128.2, 128.1, 95.5 (J = 165.8 Hz), 82.1, 67.2, 66.9, 50.8, 50.7, 42.0 (J = 21.8 Hz), 36.0, 27.8, 27.4 (J = 24.5 Hz), 26.3 (J = 25.5 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –135.4 ppm. ESI-HRMS: m/z calcd for C29H38N2O7F [M + H]: 545.2659; found: 545.2663. Compound 10 Boc-l-Lys(Cbz)-OH was directly coupled to the free amine extracted after acid cleavage of benzophenonimine derivative 3 in a solution of the free amino ester in DMF in the presence of HATU (1 equiv) and DIPEA (3 equiv). The mixture was stirred for 24 h at room temperature. The solvent was evaporated, and the residue was diluted with EtOAc and consecutively extracted with 1 M KHSO4 (2×), aqueous NaHCO3 (2×) and brine (2×), dried over Na2SO4, and the solvent was evaporated under reduced pressure to afford the crude product. Flash chromatography (SiO2, cyclohexane–EtOAc = 70:30) provided 10 as colorless oil (600 mg, 73%). 1H NMR (300 MHz, CDCl3): δ = 1.30–1.59 (m, 25 H), 1.67 (s, 3 H), 1.71–1.80 (m, 2 H), 2.36 (ddd, J 1 = 6.0 Hz, J 2 = 14.0 Hz, J 3 = 52.4 Hz, 2 H), 3.10–3.15 (m, 2 H), 4.01 (m, 1 H), 4.46 (m, 1 H), 4.67 (s, 1 H), 4.75 (t, J = 1.5 Hz, 1 H), 4.95 (br s, 1 H), 5.02 (s, 2 H), 5.06 (br s, 1 H), 6.33 (d, J = 7.1 Hz, 1 H), 7.22–7.28 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.6, 171.0, 156.5, 155.6, 140.6, 136.6, 128.5, 128.1, 128.0, 114.4, 82.2, 79.9, 66.6, 54.1, 51.0, 40.6, 40.4, 32.0, 29.3, 28.3, 27.9, 22.3, 21.9 ppm. ESI-HRMS: m/z calcd for C29H46N3O7 [M + H]: 548.3336; found: 548.3336. Compound 11 Following the same procedure described for compound 5, peptide 11 was prepared starting from precursor 10 (170 mg, 0.310 mmol) and purified by flash chromatography (SiO2, cyclohexane–EtOAc = 80:20) providing the desired compound as a colorless oil (130 mg, 74%) 1H NMR (300 MHz, CDCl3): δ = 1.36–1.64 (m, 30 H), 1.79–1.85 (m, 1 H), 1.97–2.14 (m, 2 H), 3.17–3.22 (m, 2 H), 4.09 (m, 1 H), 4.50–4.52 (m, 2 H), 5.01 (br s, 1 H), 5.09 (s, 2 H), 5.11 (br s, 1 H), 6.57 (d, J = 5.1 Hz), 7.29–7.35 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.5, 170.8, 156.5, 155.5, 136.6, 128.4, 128.1, 128.0, 95.2 (J = 165.5 Hz), 82.2, 66.6, 54.1, 50.4, 42.2 (J = 21.9 Hz), 40.4, 32.0, 29.3, 28.3, 27.8, 27.4 (J = 24.3 Hz), 26.9, 26.4 (J = 24.5 Hz), 22.2 ppm. 19F NMR (376 MHz, CDCl3): δ = –135.75 ppm. ESI-HRMS: m/z calcd for C29H47N3O7F [M + H]: 568.3399; found: 568.3398.
- 21 Teare H, Robins EG, Kirjavainen A, Forsback S, Sandford G, Solin O, Luthra SK, Gouverneur V. Angew. Chem. Int. Ed. 2010; 49: 6821
- 22 Mizuta S, Stenhagen IS. R, O’Duill M, Wolstenhulme J, Kirjavainen AK, Forsback SJ, Tredwell M, Sandford G, Moore PR, Huiban M, Luthra SK, Passchier J, Solin O, Gouverneur V. Org. Lett. 2013; 15: 2648
- 23 Richter S, Wuest F. Molecules 2014; 19: 20536
- 24a Maschauer S, Greff C, Einsiedel J, Ott J, Tripal P, Hübner H, Gmeiner P, Prante O. Bioorg. Med. Chem. 2015; 23: 4026
- 24b Mascarin A, Valverde IE, Vomstein S, Mindt TL. Bioconjugate Chem. 2015; 26: 2143
- 24c Jia Y, Shi W, Zhou Z, Wagh NK, Fan W, Brusnahan SK, Garrison JC. Nucl. Med. Biol. 2015; 42: 816