笏甲醇在無水CH2Cl2中與過量的COCl2反應(yīng)可以得到很好產(chǎn)率的Fmoc-Cl（熔點61.5-63℃），所得Fmoc-Cl在二氧六環(huán)/Na2CO3或NaHCO3溶液同氨基酸反應(yīng)則可得到Fmoc保護(hù)的氨基酸。在用Fmoc-Cl引入Fmoc的過程中二異丙基乙胺可抑制二肽的生成?；蛴肍moc-OSu(Su = 丁二酰亞胺基)在乙腈/水中導(dǎo)入，該方法在制備氨基酸衍生物時很少低聚肽生成。
氨基酸的笏甲氧羰基的導(dǎo)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%).
氨基酸的笏甲氧羰基的導(dǎo)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.
一般胺的笏甲氧羰基的導(dǎo)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.
笏甲氧羰基的脫去
Fmoc同前面提到的Cbz和Boc不同，它對酸穩(wěn)定，較易由簡單的胺不通過水解來去保護(hù)，被保護(hù)的胺以游離堿釋出。
Fmoc-ValOH在DMF中用不同的胺堿去保護(hù)的快慢有較大的差異，20%的哌啶較快。Fmoc保護(hù)基一般也能用濃氨水、二氧六環(huán)/4M NaOH(30:9:1)以及用哌啶、乙醇胺、環(huán)己胺、嗎啡啉、吡咯烷酮、DBU等胺類的50%CH2Cl2的溶液脫去。另外，Bu4N+F-/DMF在室溫的脫去效果也很好。叔胺（如三乙胺）的脫去效果較差，具有空間位阻的胺的脫除效果最差。
二乙胺用于脫除笏甲氧羰基示例
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%).
哌啶用于脫除笏甲氧羰基示例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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