Novel N,S-Phenacyl Protecting Group and Its Application for Peptide ­Synthesis

Abstract

The phenacyl group can be introduced onto amino and thio groups by N,S-alkylation reactions. Conversely, these groups are removed rapidly by employing magnesium in acetic acid. This protecting group was successfully applied to a short peptide synthesis of Boc-l-Cys-Gly-OMe.

Key words

protecting groups - alkyl halides - magnesium - peptides - thiols

References and Notes

• 1 Yang CC. Merrifield RB. J. Org. Chem.  1976,  41:  1032 
• 2 Stelakatos GC. Zervas L. J. Chem. Soc. C.  1966,  1191 
• 3 Fletcher AR. Jones JH. Ramage WI. Stachulski AV. J. Chem. Soc., Perkin Trans. 1  1979,  2261 
• 4 Sheehan JC. Daves GD. J. Org. Chem.  1964,  29:  2006 
• 5 Tam JP. Cunningham-Rundles WF. Erickson BW. Merrifield RB. Tetrahedron Lett.  1977,  4001 
• 6a Ueki M. Kai K. Amemiya M. Horino H. Oyamada H. J. Chem. Soc., Chem. Commun.  1988,  414 
• 6b Namikoshi M. Kundu B. Rinehart KL. J. Org. Chem.  1991,  56:  5464 
• 7 Sheehan JC. Umezawa K. J. Org. Chem.  1973,  21:  3771 
• 8 Ram RN. Singh L. Tetrahedron Lett.  1995,  36:  5401 
• 9 Hyat JA. J. Org. Chem.  1972,  37:  1255 
• 10 Kakinaki S. Leondiadis L. Ferderigos N. Org. Lett.  2005,  7:  1723 
• 11 Hendrickson JB. Kandall C. Tetrahedron Lett.  1970,  343 
• 12 Hendrickson JB. Bergeron R. Tetrahedron Lett.  1970,  345 
• 13 Eckert H. Listl M. Ugi I. Angew. Chem., Int. Ed. Engl.  1978,  17:  361 
• 14 Kende AS. Mendoza JS. Tetrahedron Lett.  1990,  31:  7105 

15

Synthesis of Substrate Materials 1-12; Typical Protection Procedure To an ice-cooled solution of amino or thio compound (5 mmol) in EtOAc (20 mL) was added Et₃N (0.55 g, 5.5 mmol) and phenacyl bromide (1.1 g, 5.5mmol). After stirring at r.t. for 4 h, the reaction mixture was diluted with EtOAc (25 mL). The organic layer was washed with brine (10 mL), sat. NaHCO₃ (10 mL), brine (2 × 10 mL), dried over Na₂SO₄, and filtered. The filtrate was evaporated in vacuo and the crude product was purified by silica gel chromatography using a mixture of PE-EtOAc.

Typical Deprotection Procedure
To a solution of the protected substrate (2 mmol) in MeOH (15 mL) was added AcOH (1.5 mL, 24 mmol) and Mg turnings (288 mg, 12 mmol). The solution was stirred for 50-70 min (followed by TLC) at r.t. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was diluted with 5% NaHCO₃ (10 mL), EtOAc (2  10 mL), and combined organic solution. The organic layer was washed with brine (2  10 mL), dried with Na₂SO₄, and filtered. The filtrate was evaporated in vacuo. The crude product was purified by silica gel chromatography using a mixture of PE-EtOAc.
N -[ N -( tert -Butoxycarbonyl)- S -(phenacylthio)cyste-inyl]glycine Methyl Ester (15)
Brown solid. ^¹H NMR (400 MHz, CDCl₃): d = 1.44 (s, 9 H), 2.89-2.99 (m, 2 H), 3.73 (s, 3 H), 3.97-4.08 (m, 4 H), 4.49 (s, 1 H), 5.64 (d, J = 8.0 Hz), 7.30 (s, 1 H), 7.30-7.49 (m, 2 H), 7.57-7.61 (m, 1 H), 7.96-7.98 (m, 2 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): d = 195.2, 170.8, 169.8, 155.6, 135.2, 133.6, 128.7, 128.6, 80.3, 53.3, 52.3, 41.2, 38.3, 34.9, 28.2 ppm. ESI-MS: m/z = 411.2 [M + H]⁺, 433.1 [M + Na]⁺; [a]_D ^²0 -19.3 (c 1, MeOH). ESI-HRMS: m/z calcd for [C₁₉H₂₆N₂O₆S + Na]⁺: 433.1409; found: 433.1411; for [C₁₉H₂₆N₂O₆S + H]⁺: 411.1590; found: 411.163.
N -[ N -( tert -Butoxycarbonyl)cysteinyl]glycine Methyl Ester (16) Clear oil. ^¹H NMR (400 MHz, CDCl₃): d = 1.46 (s, 9 H), 1,69 (dd, J = 7.6, 2.8 Hz), 2.73-2.75 (m, 1 H), 3.11-3.15 (m, 1 H), 3.76 (s, 3 H), 3.99-4.13 (m, 2 H), 4.42 (s, 1 H), 5.54 (d, J = 7.6 Hz, 1 H), 6.96 (s, 1 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): d = 170.5, 169.9, 155.4, 128.1 125.6, 80.9, 55.4, 52.4, 41.2, 28.2, 28.1, 26.9 ppm. ESI-MS: m/z = 293.1 [M + H]⁺, 315.1 [M + Na]⁺.