发布时间 : 星期六 文章氨基的保护及脱保护更新完毕开始阅读f72c97b71611cc7931b765ce0508763230127459
573; M. A. Schwartz, B. F. Rose et al., J. Am. Chem. Soc., 1973, 95, 612; D. L. Boger, D. Yohannes., J. Org. Chem., 1989, 54, 2498 3. M. Imazawa, F. Eckstein., J. Org. Chem., 1979, 44, 2039 4. S. B. King, B. Ganem., J. Am. Chem. Soc., 1994, 116, 562
5. D. Albanese, F. Corcella, D. Landini et al., J. Chem. Soc. Perkin Trans. I, 1997, 247
3.3.2.1 KOH脱去三氟乙酰基示例
Chambers, James J; Parrish, Jason C et al., J. Med. Chem., 2003, 46(16),
3526-3535
A solution of compound 1 (1.7 g, 5.4 mmol) in MeOH (250 mL) was cooled to 0°C, and then 5 N KOH solution (30 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred overnight, and then the MeOH was removed by rotary evaporation. The residue was diluted with H2O (25 mL) and extracted with Et2O (4 x 100 mL), dried (Na2SO4), filtered, and evaporated to afford clear oil. This oil was dissolved in Et2O (100 mL), filtered through a plug of glass wool, and neutralized by the slow addition of oxalic acid (54 mL, 0.1 M in MeOH). The solvents were removed, and the resulting white residue was recrystallized from MeOH to afford compound 2 (0.9 g, 59%) as the hemioxalate salt, m.p 243 °C.
3.3.2.2 K2CO3脱去三氟乙酰基示例
Whitlock, Gavin A; Carreira, Erick M et al., Helv. Chim. Acta., 2000, 83(8),
2007-2022
Compound 1 (45 mg, 0.18 mmol) was dissolved in 5% K2CO3 in MeOH/H2O (15 mL), and the soln. was stirred at 23°C for 4 h. H2O (3 mL) was added, the soln. was saturated with NaCl, and then extracted with CH2Cl2 (5×15 mL). The combined org. extracts were dried (Na2SO4) and concentrated under reduced pressure to afford compound 2 (23.5 mg, 85%).
4．烷基类
4.1 三苯甲基（Trt）
三苯甲基（Trt）是50年代开始用于多肽合成的，现在体积大的Trt被用于保护各种氨基，如氨基酸、青霉素、头孢霉素等。N-Trt-α-氨基酸的酯不能发生水解，需要较强的去保护条件，α-质子同样不易被脱去，这意味着，在分子中其他地方的酯可以选择性的水解。
Trt的立体位阻的影响还表现在接肽反应中，Trt-氨基酸（除Trt-Gly和Trt-Ala以外）一般不能采用混合酸酐法接肽[1]，Trt-氨基酸的酯不能水解，也就不能用叠氮法接肽，而只能采用DCC这类方法来接肽。但Trt的立体位阻只表现在对Trt-氨基酸的反应影响上，Trt-肽则不存在这个问题，因此对长链肽的末端氨基的保护来说，Trt还是可用的，特别是对于带有含硫氨基酸的肽来说，由于不能采用催化氢解来实现Cbz和Boc之间的选择性脱去，采用Trt则将有其有利之处。
1. L. Zervas, D. M. Theodoropoulos., J. Am. Chem. Soc., 1956, 78, 1359 4.1.1 三苯甲基的引入
由于Trt有很大的立体位阻，除氨基酸侧链很小的Trt-甘氨酸酯以外，一般的Trt-氨基酸酯都难以皂化，而用很强烈的条件（如高温）则有引起消旋的危险。因此Trt的引入一般是采用以下反应来实现的。
尽管可采用先制得Trt-氨基酸苄酯，然后控制吸收1.1当量的氢选择性氢解的方法，但由于总有部分Trt被氢化，因此需要除去所生成的自由氨基酸副产物。玉置等人曾经提出[1]，将氨基酸悬浮与CHCl3中，加入2.2当量的Trt-Cl和2.2当量的Et3N，搅拌反应5-10小时先生成Trt-氨基酸三苯甲酯，然后用HCl/HOAc处理5-20分钟脱去三苯甲酯而得到Trt-氨基酸。另一个办法是用肽的酯同Trt-Cl反应得到Trt-肽酯，后者容易皂化而不存在Trt的立体位阻作用。吡咯、吡唑和咪唑等也可用类似反应容易地得到良好产率的Trt-衍生物。另外，利用Trt-Cl/Me3SiCl/Et3N[2]和Trt-Cl/TMSCl/Et3N[3]也容易得到Trt-氨基酸。
1. 玉置健太郎，工藤士郎., 有机合成协会志., 1971, 29, 599
2. Hoffman, Robert V; Maslouh, Najib et al., J. Org. Chem., 2002, 67(4), 1045-1056; Sim, Tae Bo; Rapoport, Henry et al., J. Org. Chem., 1999, 64(7), 2532-2536
3. Hoffman, Robert V; Tao Junhua, J. Org. Chem., 1998, 63(12), 3979-3985 4.1.1.1 氨基酸的三苯甲基的引入示例
Hoffman, Robert V; Maslouh, Najib et al., J. Org. Chem., 2002, 67(4), 1045-1056 Chlorotrimethylsilane (1.27 mL, 10.0 mmol) was added at room temperature to a stirred suspension of an compound 1 (1.61 g, 10.0 mmol) in 18 mL of CHCl3/MeCN (5:1). The reaction mixture was refluxed for 2 h and then cooled to 0 °C. Dropwise addition of triethylamine (2.79 mL, 20.0 mmol) was followed by a solution of trityl chloride (2.79 g, 10.0 mmol) in chloroform (10 mL). The resulting mixture was stirred for 1 h, and then methanol (2 mL) was added. After concentration, the pale yellow residue was partitioned between diethyl ether and water. The aqueous layer was extracted twice with diethyl ether (20 mL). The combined organic layers were dried (MgSO4) and concentrated to give compound 2 (2.14 g, 53%), which was used for the next step without further purification. 4.1.1.2 氨基醇的三苯甲基的引入示例
Gros, Christel; Boulegue, Cyril et al., Tetrahedron, 2002, 58(13), 2673-2680 Amino alcohol 1 (2.15 g, 12.3 mmol) and Et3N were dissolved in dry CH2Cl2 (60 mL). To the ice-bath cooled preceding solution, trityl chloride (3.43 g, 12.3 mmol) dissolved in CH2Cl2 (20 mL) was added dropwise over 15 min. After stirring 1 h at rt, the solvent was evaporated. The residue dissolved in AcOEt (100 mL) and followed by a flash column chromatography purification (AcOEt/cyclohexane 80:20) to afford alcohol 2 as an oil in: 83% yield. 4.1.2 三苯甲基的脱去
Trt容易用酸脱去，如用HOAc或50%（或75%）HOAc的水溶液在30℃或回流数分钟顺利除去。这时N-Boc和O-But可以稳定不动[1]。其他如HCl/MeOH[2]、HCl/CHCl3、HBr/HOAc和TFA[3]都能很方便的脱去Trt，用HCl/MeOH处理Trt-Lys(Trt)OCH3可以得到Lys(Trt)OCH3，说明侧链上的Trt比α-Trt 对酸更稳定一些。Cys(Trt)、His(Trt)和Try(Trt)等的侧链上的N-Trt比Nα-Trt 对酸稳定，因此可以采用适当的酸解条件选择性脱去Nα-Trt而保留侧链上的N-Trt。
Trt对酸的敏感程度还随所用的酸的不同而异，例如Trt对醋酸比较敏感，在80%的醋酸中，Trt的脱除速度大约比Bpoc快7倍，比Boc快21，000倍，因而可以在Boc或Moz存在下选择性地脱去Trt。但如用0.1M HBr/HOAc为试剂，Trt脱去速度反而慢
[4]
于Boc和Moz。
Trt也能被催化氢解脱去[5]，但脱去速度比O-苄基和N-Cbz要慢得多。根据所用试剂和脱去方法得不同，Trt被分解所形成的产物也不同（见下式）。
[1]
1. 1. L. Zervas, D. M. Theodoropoulos., J. Am. Chem. Soc., 1956, 78, 1359; F. C. McKay, N. F. Abertson., J. Am. Chem. Soc., 1957, 79, 4686; R. Schwyzer, W. Rittel., Helv. Chim. Acta., 1961, 44, 159
2. L. Hyun-Suk, P. Jeong-Ju et al., Bioorg. Med. Chem. Lett., 2004, 10, 2499;
K. Yuji, T. Ryuichi et al., Bioorg. Med. Chem., 2002, 10, 3829
3. S. Rita, K. Yeong-Sang et al., Tetrahedron Lett., 2003, 8, 1537 4. B. Bezas, L. Zervas., J. Am. Chem. Soc., 1961, 83, 719; G. Amiard, B. G. Offinet., Bull. Soc. Chim. France., 1956, 698
5. Chandrasekhar, S., Babu, B. Nagendra et al., Tetrahedron Lett., 2003, 10,
2057; E. Janos, K. Gyoergy et al., Tetrahedront., 2002, 44, 8921 4.1.2.1
TFA脱去三苯甲基示例
M. Firouz Mohd Mustapa, Richard Harris, Nives Bulic-Subanovic et al., J. Org. Chem., 2003, 21, 8185; S. Vinay, M. Mizio et al., Tetrahedron, 2002, 44, 9101 Compound 1 (3.5 g, 4.6 mmol) was treated with a 5% solution of trifluoroacetic acid (1.4 mL, 18 mmol, 4 equiv) in CHCl3 (27 mL) under inert conditions for 4 h. The resulting solution was diluted with CHCl3 (200 mL) and washed with sodium hydrogen carbonate (5% aq w/v, 2 × 75 mL) and water (2 × 50 mL). The solvent was removed in vacuo. The material was then redissolved in CHCl3 (20 mL) and MeOH (20 mL), and the solvents were again removed in vacuo to yield compound 2 (2.1 g, 87%) as a pale yellow liquid. 4.1.2.2 TFA-TIS脱去三苯甲基示例
Swall, Vinay; Matteuccl et al., Tetrahedron, 2002, 58(44), 9101-9110 Compound 1 (2.0 g, 2.71 mmol) was stirred with TFA (4.9mL), CH2Cl2 (4.9mL) and TIS (0.2 mL) for 1 h. Solvent was removed in vacuo and the residue purified