芴[wù]甲氧羰基保护氨基

芴甲醇在无水CH2Cl2中与过量的COCl2反应可以高产率得到Fmoc-Cl（熔点61.5-63℃），所得Fmoc-Cl在二氧六环/Na2CO3或NaHCO3溶液同氨基酸反应则可得到Fmoc保护的氨基酸。在用Fmoc-Cl引入Fmoc的过程中二异丙基乙胺可抑制二肽的生成。或用Fmoc-OSu(Su=丁二酰亚胺基)在乙腈/水中引入，该方法在制备氨基酸衍生物时很少有低聚肽生成。

氨基酸的芴甲氧羰基的导入示例1

R. J. Malene; A. O. Christian et al., J. Med. Chem., 2005, 1, 56

A solution of Fmoc-Cl (31 g, 0.12 mol) in dioxane (150 ml) was added to a suspension of compound 1 (24.1 g, 0.1 mol)in dioxane (100 ml) and 10% aqueous Na2CO3 (150 ml) at 0°C. The mixture was stirred for 1 h at 0°C and then for 1 h at room temperature. The reaction mixture was poured into water and washed with Et2O. The aqueous phase was acidified with concentrated aqueous HCl, and the precipitated product was isolated by filtration and dried in vacuo to give compound 2 (45 g g, 98%).

氨基酸的芴甲氧羰基的导入示例2

Carrasco, Michael R; Brown, Ryan T et al., J. Org. Chem., 2005, 68(1), 195-197

Compound 1 (1.25 mmol), were dissolved in DMF (30 mL) and H2O (30 mL), treated with NaHCO3 (210 mg, 2.5 mmol) and Fmoc-OSu (464 mg, 1.37 mmol), and stirred for 24 h. The solvents were removed, and the residue was dissolved in EtOAc (150 mL) and washed with 0.1 M KHSO4 (4 x 50 mL), H2O (4 x 50 mL), and brine (100 mL). After drying and removal of the solvent, the residue was chromatographed (acetone:CH2Cl2:AcOH, 5:95: 0.5 to 10:90:0.5) and then purified by size exclusion chromatography (LH-20, CH2Cl2) to yield compound 2 (456 mg, 0.969 mmol, 78%) as a glassy solid.

一般胺的芴甲氧羰基的导入示例

R. A. Tromp; M. V. D. Michael et al., Tetrahedron: Asymmetry, 2003, 12, 1645

To a vigorously stirred mixture of 3 mL of dichloromethane and 6 mL of saturated NaHCO3 (aq.) and 1mmol of 4 was added 1.4 equiv. of Fmoc-Cl. After the reaction had come to completion (TLC), 6 mL of dichloromethane and 3 mL of water were added, and the layers separated. The organic phase was washed once with brine, dried (MgSO4), and the solvent evaporated. The crude compound was purified by column chromatography (pet. ether 40–60/EtOAc 95/5, v/v) to yield 5e in 79% yield as a white solid, mp 88°C.

芴甲氧羰基的脱去

Fmoc同Cbz和Boc不同，它对酸稳定，较易由简单的胺不通过水解来去保护，被保护的胺以游离碱释出。

Fmoc-ValOH在DMF中用不同的胺碱去保护的快慢有较大的差异，20%的哌啶较快。Fmoc保护基一般也能用浓氨水、二氧六环/4M NaOH(30:9:1)以及用哌啶、乙醇胺、环己胺、吗啡啉、吡咯烷酮、DBU等胺类的50%CH2Cl2的溶液脱去。另外，Bu4N+F-/DMF在室温的脱去效果也很好。叔胺（如三乙胺）的脱去效果较差，具有空间位阻的胺的脱除效果最差。

二乙胺用于脱除芴甲氧羰基示例

Shu-Li You and Jeffery W. Kelly., J. Org. Chem. 2003, 68, 9506

Diethylamine (30 mL) was added to a solution of 5 (5.63 g, 9 mmol) in CH3CN (30 mL), and the resulting mixture was stirred at 25 °C for 30 min to ensure complete removal of the Fmoc protecting group. After concentration in vacuo, the reaction mixture was azeotroped to dryness with CH3CN (2 x 30 mL) to give compound 2 (3.4 g, 89%).

哌啶用于脱除芴甲氧羰基示例1

US6329389

Piperidine (0.66 ml) was addede to a solution of compound 1 (0.797 g) in MeOH (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 h, then concentrated and the residue was purified by alumina column chromatography (rthyl acetate/methanol = 10/1) to obtain compound 2 (0.382 g, 76%).

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