发布时间 : 星期一 文章氨基的保护及脱保护更新完毕开始阅读f72c97b71611cc7931b765ce0508763230127459
2. F. M. F. Chen, N. L. Benoiton., Can. J. Chem., 1987, 65, 1224 2.3.1.1.1 氨基酸的笏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%).
2.3.1.1.2 氨基酸的笏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. 2.3.1.2.3 氨基酸酯的笏甲氧羰基的导入示例
R. J. Malene; A. O. Christian et al., J. Med. Chem., 2005, 1, 56 Compound 1 (197 mg, 0.726 mmol) was suspended in a mixture of MeCN (10 mL) and 10% aqueous Na2CO3 (15 mL), and the mixture was stirred overnight at room temperature, followed by stirring for 16 h at 40 °C. MeCN was removed in vacuo, and dioxane (20 mL) and Fmoc-Cl (188 mg, 0.726 mmol) in dioxane (3 mL) were added successively at 0 °C. The mixture was stirred at 0 °C for 1 h and was then poured into water (100 mL). The resulting mixture was washed with hexane (50 mL), and the aqueous phase was acidified with 4 M aqueous HCl and extracted
with EtOAc (4 x 50 mL). The combined EtOAc phases were dried (Na2SO4), filtered, and concentrated. Purification by TLC (hexanes-EtOAc 2:1 to hexanes-EtOAc-HOAc 1000:1000:1) afforded compound 2 (237 mg, 68%) as a syrup. TLC: Rf 0.20 (hexanes-EtOAc-HOAc 1000:1000:1).
2.3.1.2 一般胺的氨基酸酯的笏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. 2.3.2 笏甲氧羰基的脱去
Fmoc同前面提到的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[1]。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[2]。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[3]。
1. For a review of the use of Fmoc protection in peptide synthesis, see E. Atherton and R. C. Sheppard, ‘The Fluorenylmethoxycarbonyl Amino Protecting Group’, in The Peptides, S. Udenfriend and J. Meienhofer, Eds., Academic Press, New York, 1987, 9, 1
2. M. Ueki, M. Amemiya., Tetrahedron Lett., 1987, 28, 6617
3. L. A. Carpino, G. Y. Han., J. Am. Chem. Soc., 1970, 92, 5748; C. D. Cheang et al., Int. Pept. Prot. Res., 1980, 15, 59 2.3.2.1 三乙胺用于脱除笏甲氧羰基示例
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%).
2.3.2.2 20%的哌啶用于脱除笏甲氧羰基示例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%).
US6331640
Piperidine (0.88 ml, 0.89 mmol) was addede to a solution of compound 1 (116 mg, 0.18 mmol) in DMF (5 ml) at room temperature. The solution was stirred at room temperature for 30 min, and then solvent was evaporated. The resulting white solid was triturated with ether five times and dried in vacuo to give compound 2 (59 mg, 81%) as an off-white solid.
2.4. 烯丙氧羰基（Alloc）
烯丙氧羰基（Alloc）同前面提到的Cbz、Boc和Fmoc不同，它对酸、碱等都很稳定，在它的存在下，Cbz、Boc和Fmoc等可选择性去保护，而它的脱去则通常在Pd(0)的存在下进行。
2.4.1 烯丙氧羰基（Alloc）的引入
Alloc-Cl在有机溶剂/Na2CO3、NaHCO3溶液或吡啶中同氨基化合物反应则可得到Aloc保护的氨基衍生物[1]。
1. E. J. Corey, J. W. Suggs., J. Org. Chem., 1973, 38, 3223 2.4.1.1氨基酸的烯丙氧羰基（Alloc）的引入示例
Micale, Nicola; Vairagounder, Rajendran et al J. Med. Chem., 2004, 47(26),
6455-6458
To a stirred solution of compound 1 (3.0 g, 15.86 mmol) in a mixture of aq. NaHCO3 and THF (8/2, 20 mL) was added allylchloro formate (2.54 mL, 23.81 mmol), dropwise and at 0 °C. The mixture was stirred at room temperature for 12 h and then diluted with ethyl acetate and washed 3 N HCl, dried and the solvent removed in vacuo to give compound 2 as a pale yellow oil, which was used without further purification (3.55 g, 82%).
2.4.1.2一般氨基的烯丙氧羰基（Alloc）的引入示例
H. Imamura; A. Shimizu et al., Tetrahedron, 2000, 56(39), 7705
To a solution of 17 (1.0 g, 1.97 mmol) in EtOAc (10 ml) was added 4 M HCl/EtOAc (20 mL), and the mixture was stirred for 6 h at room temperature. After evaporation, to the suspension of the residue in CH2Cl2 (40 mL) were added triethylamine (2.75 mL, 19.7 mmol) and allyl chloroformate (0.627 mL, 5.91 mmol) at -10°C. The reaction mixture was poured into H2O and the whole was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/acetone = 8:1) to give 18 (863 mg, 92.1%) as a foam. [ a]D25=19.6 (c =1.0, CHCl3). 2.4.2 烯丙氧羰基（Alloc）的脱去
Alloc保护基对酸、碱等较强的稳定性，它们通常只用Pd(0)，如Pd(PPh3)4或Pd(PPh3)2Cl2存在的条件去保护。例如，Alloc衍生物用Pd(PPh3)4/Me2NTMS处理，可以得到易水解的氨基甲酸TMS酯 [1]。脱去含硫衍生物中的Alloc 时，如蛋氨酸，Pd(PPh3)4/二甲基环己二酮/TH则不会被毒化[2]。如果在酸性条件下脱除Alloc，则最好采用Pd(PPh3)2Cl2/Bu3SnH/p-NO2C6H4OH/CH2Cl2。在异戊烯酯或肉桂酸酯存在下，可用Pd(OAc)2/TPPT/CH3CN/Et3N/H2O去保护，但随时间的增加，这些酯也会反应，并且氨基甲酸异戊烯酯和烯丙基碳酸酯同样被断裂[4]。当加入Boc2O、AcCl、TsCl、或丁二酸酐时，Pd(PPh3)2Cl2/Bu3SnH可将Alloc基转变为其它的胺衍生物。另外，Alloc也可在Pd(PPh3)4/HCOOH/TEA[5]或AcOH/NMO催化脱去[6]。
1. A. Merzouk, F. Guibe., Tetrahedron Lett., 1992, 33, 477
[3]