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2.2.2.5.3 叔丁酯存在下的脱Boc示例3
NHBocOOOOOTFACH2Cl2OOOONH2O12
WO20040106286
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
NHOEtOOCH(neat)MeONBoc1MeO2NHNHHOEtOOCHNHNHH
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]。
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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 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
OHONH2Fmoc-Claq. Na2CO312HOONHFmoc
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%).
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2.3.1.1.2 氨基酸的笏甲氧羰基的导入示例2
OOONOOOH2NOHO1OFmocHNOHO2BocNBocNNaHCO3, DMF(Fmoc-OSu)
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
OOFmoc-Cl10%Na2CO3CH3CNFmocHNCOOMe1NCOOH2
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).
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2.3.1.2 一般胺的氨基酸酯的笏甲氧羰基的导入示例
OTBSOH2NOTBSFmoc-Clsat. NaHCO3CH2Cl2OHNFmoc
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。
NH2+R1R2OOHNR1R2HN
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
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