发布时间 : 星期日 文章氨基的保护及脱保护更新完毕开始阅读f72c97b71611cc7931b765ce0508763230127459
added TBDMSOTf (0.9 mL, 4.1 mmol). After stirring the reaction mixture for 6 h, the solvent was evaporated, and the crude product (0.8 g, 75%) was obtaineded, which was used directly in the next step.
2.2.2.1.2 TMSOTf-2,6-lutidine中性条件下脱Boc示例1
Kemp, Scott J; Bao, Jiaming et al J. Org. Chem., 1996, 61(20), 7162-7167 To a stirring solution of compound 1 (800 mg, 2.0 mmol) and 2,6-lutidine (0.4463 ml, 4.0 mmol) in CH2Cl2 (6 mL) was added tert-butyldimethylsilyl triflate (0.690 ml, 3.0 mmol) dropwise over 5 min. After 20 min, saturated NH4Cl (10 mL) was added. The mixture was stirred and separated, and the aqueous layer was extracted with Et2O (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL) and saturated NaCl (10 mL), dried (MgSO4), and concentrated to give the crude silyl carbamate, which was dissolved in THF (10 mL) and cooled to 0°C. A 1.0 M solution of TBAF in THF (2 mL, 2 mmol) was added over 5 min, and then the solution was stirred at 0°C for 1 h. The solution was concentrated and chromatographed (95:5 CH2Cl2-methanol) through a small plug of silica to give compound 2 (882 mg, 75%) as a clear oil. 2.2.2.1.3 TMSOTf-2,6-lutidine 条件下脱Boc示例2
Sakaitani, Masahiro; Ohfune, Yasufumi; J. Org. Chem., 1990, 55(3), 870-876 To a stirred solution of compound l (500 mg, 1.52 mmol) and 2,6-lutidine (0.353 ml, 3.04 mmol) in dry CH2C12 (3.0 mL) at 0 \t-BuMe2SiOTf (0.523 ml, 2.28 mmol). The reaction mixture was stirred at 0°C for 15 min, quenched with saturated aqueous ammonium chloride solution, and extracted with ether several times. The combined organic phase was washed with H2O and then brine, dried (MgSO4), and concentrated in vacuo to give an oily residue, which upon purification by column chromatography on silica gel (elution with 50% ether in hexane) gave O-silyl ester compound 2 (652 mg, 97%): colorless needles; mp 64.0-65.0°C (hexane). 2.2.2.2 TFA脱Boc示例
M. Alberto; A. Eduardo et al., J. Org. Chem., 2004, 21, 7004
To a solution of the β-aminoester (0.2 mmol) in CH2Cl2 (3 mL), cooled to 0°C was added TFA (1mL). After the consumption of the starting material (45 min, monitored by TLC), the mixture was evaporated and then saturated aqueous NaHCO3 was added. The aqueous layer was extracted twice with CH2Cl2 (15 mL), and the organic layer washed with brine and dried over anhydrous Na2SO4. The solvent was removered under vacuum, to afford the amine, which were employed without further purification to prepare the Mosher’s diastereoisomeric amides. 2.2.2.3 HCl-Et2O脱Boc示例
C. Mühlemann, P. Hartmann, J. P. Obrecht., Org. Syn., 71, 200
tert-Butyl [1-(tert-butoxycarbonyl)-3-oxo-4-pentenyl]carbamate, 8.73 g (0.0308 mol), is dissolved in 280 mL of an ice-cooled, saturated solution of hydrogen chloride in ether. The solution is kept without stirring at room temperature overnight. The resulting suspension is filtered and the filter cake is immediately washed with dry ether. The washing with ether is repeated four times and, after drying under reduced pressure, 5.48 g (99%) of 4-ketopipecolic acid hydrochloride is obtained as a colorless powder, mp 139–142°C dec. 2.2.2.4 HCl-THF脱Boc示例
J. Wehbe et al., Tetrahedron: Asymmetry, 2004, 15, 851
To the Boc protected amine (0.06 g, 0.17 mmol) dissolved in THF (1mL) was added 2M HCl (1mL, 2 mmol) and the mixture stirred 2 h at room temperature. After evaporation of the solvent, the product was extracted into EtOAc (3. 5mL). The organic layer was dried and evaporated under vacuum to afford 17b in 95% yield as a white solid.
2.2.2.5.1 叔丁酯存在下的脱Boc示例1
US5610144
1.77 ml of Me3SiI are added dropwise at room temperature in the vicinity of 25°C to a soution of 3.8 g of compound 1 in 50 ml of CHCl3. Stirring is contiuned for 30 min, then 20 ml f water are addede. The aqueous phase is separated, then extracted with CHCl3(2 x 20 ml). The organic phases are combined, washed successively with a saturated aqueous Na2CO3(30 ml) and water(2 x 30 ml), then dried over MgSO4 and concentrated to dryness under reduced pressure at 40°C. The mixture of the two diastereoisomers obtained is separated by chromatography on silica (eluent: ethyl acetate/cyclohexane = 1/4). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40°C to give compound 2 (0.5 g), as a yellow-orange oil, used as it is in subsequent syntheses. 2.2.2.5.2 叔丁酯存在下的脱Boc示例1
To asolution of compound 1 (6.3 g, 21.0 mmol) in ethyl acetate (50 ml) was added 1.1 M HCl in ethyl acetate (28.7 ml, 31.5 mmol). The reaction was stirred at room temperature for 1 h, then washed with water, saturated aq. NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and evaporated to afford compound 2 (3.11 g, 74%) as a yellow oil which crystallized upon standing.
2.2.2.5.3 叔丁酯存在下的脱Boc示例3
To a solution of compound 1 (149 mg, 0.33 mmol) in CH2Cl2 (2 ml), TFA (1 ml) as added at 0°C and the mixture was stirred for 1 h at 0°C. Saturated aqueous Na2CO3 was added and the mixture was etracted with CHCl3. The etract was purified by silica gel column chromatography to obtained compound 2 (92 mg, 79%). 2.2.2.6 吲哚环上Boc直接加热脱除示例
G. Tong; P. Ruiyan et al., J. Org. Chem., 1997, 26, 9298
Compound 1 (62 mg)was heated (neat) at 160-180 °C for 45 min. The residue was purified by flash chromatography (silica gel, CHCl3/MeOH 95/5) to afford Compound 2 (25 mg) as a solid in 50% yield. 11: [R]27D= - 65.9 (c = 0.97, in CHCl3).
2.3 笏甲氧羰基（Fmoc）
Fmoc保护基的一个主要的优点是它对酸极其稳定，在它的存在下，Boc和苄基可去保护。Fmoc的其他优点是它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[1]。一般而言Fmoc对氢化稳定，但某些情况下，它可用H2/Pd-C在AcOH和MeOH仲脱去[2]。Fmoc保护基可与酸脱去的保护基搭配而用于液相和固相的肽合成[3]。 1. L. A. Carpino., Acc. Chem. Res. 1987, 20 401; L. A. Carpino, D. Sadat-Aalaee et al., J. Org. Chem., 1990, 55, 1673
2. E. Atherton, C. Bury et al., Tetrahedron Lett., 1979, 3041
3. C. A. Bodanszky rt al., J. Org. Chem., 1980, 45, 72; J. Meienhofer et al.,
J. Pept. Prot. Res., 1978, 11, 246; J. Martinez, J. C. Tolle et al., J. Org. Chem., 1979, 44, 5396; R. B. Merrifield, A. E. Bach., J. Org. Chem., 1978, 43, 4808
2.3.1笏甲氧羰基的导入
笏甲醇在无水CH2Cl2中与过量的COCl2反应可以得到很好产率的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[1]。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[2]。或用Fmoc-OSu(Su = 丁二酰亚胺基)在乙腈/水中导入，该方法在制备氨基酸衍生物时很少低聚肽生成。
1. L. A. Carpino, G. Y. Han., J. Org. Chem., 1972, 37, 3404