三苯甲基保护氨基

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，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。

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，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和Trt-Cl/TMSCl/Et₃N也容易得到Trt-氨基酸。

 氨基酸的三苯甲基的引入示例

Hoffman, Robert V; Maslouh, Najibet 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, 10.0mmol) in 18 mL of CHCl₃/MeCN (5:1). The reaction mixture was refluxed for 2 h andthen cooled to 0 °C.Dropwise addition of triethylamine (2.79 mL, 20.0 mmol) was followed by asolution 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 yellowresidue was partitioned between diethyl ether and water. The aqueous layer wasextracted twice with diethyl ether (20 mL). The combined organic layers weredried (MgSO₄) and concentrated to give compound 2 (2.14 g, 53%), which was used for the next step withoutfurther purification.

 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

Aminoalcohol 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 solventwas evaporated. The residue dissolved in AcOEt (100 mL) and followed by a flashcolumn chromatography purification (AcOEt/cyclohexane 80:20) to afford alcohol 2 as an oil in: 83% yield.

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-tBu可以稳定不动。其他如HCl/MeOH、HCl/CHCl₃、HBr/HOAc和TFA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N^α-Trt 对酸稳定，因此可以采用适当的酸解条件选择性脱去N^α-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脱去速度反而慢于Boc和Moz。

Trt也能被催化氢解脱去，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）。

一、TFA脱去三苯甲基示例

M. Firouz Mohd Mustapa,RichardHarris,Nives Bulic-Subanovic et al., J. Org. Chem., 2003,21, 8185;  S. Vinay, M. Mizio etal., 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 resultingsolution was diluted with CHCl₃(200 mL) andwashed with sodium hydrogen carbonate (5% aq w/v, 2 × 75 mL) and water (2 × 50mL). The solvent was removed in vacuo. The material was then redissolved in CHCl₃(20 mL) and MeOH (20 mL), and the solvents were againremoved in vacuo to yield compound 2(2.1 g, 87%) as a pale yellowliquid.

二、 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. Solventwas removed in vacuo and the residue purified by column chromatography (SiO₂, MeOH/CHCl₃, 1:9 v:v) toafford compound 2 (1.16 g,91%) as a white solid.

三、TFA-Et₃SiH脱去三苯甲基示例

Pickersgill, I.Fraser; Rapoport, Henry; J. Org. Chem., 2000,65(13), 4048-4057

To a stirred solution of compound 1(3.34 g, 3.82 mmol) and triethylsilane (0.64 mL, 4.01mmol) in CH₂Cl₂(16 mL) cooled to 0 °C was added dropwise TFA (16 mL). Theresultant colorless solution was allowed to warm to rt, with stirring continuedfor 1 h. The solvents were evaporated, the residue was triturated with hexanes(5 x 50 mL), the hexane extracts were discarded, and the oily residue waspartitioned between CHCl₃/IPA (250 mL, 3/1) and 1 M NaOH (precooled to 0 °C,100 mL). The aqueous phase was extracted with further portions of CHCl₃/IPA (2 x 200mL, 3/1), and the combined organic phase was dried, filtered, and evaporated togive compound 2(2.04 g, 100% crude yield) as a pale yellowoil.

4.1.2.4 HOAc脱去三苯甲基示例

Vago, Istvan; Kalaus, Groergy et al., Heterocycles, 2001, 55(5), 873-880

0.85 g (2 mmol) of compound 1 wasdissolved in the mixture of 20 mL of acetic acid and 0.5 mL of water. The solutionwas heated under argon at 60 ºC for 1 h, and then allowed to cool to rt. Theresulted dark solution was diluted with 200 mL of water; the triphenylmethanolwas removed by extraction with ether. The pH of the watery phase was adjustedto a value of 8 with sodium carbonate solution, extracted with dichloromethane;the extract was dried with magnesium sulfate, evaporated to dryness in vacuumtogive, compound 2 (0.24 g,64 %) as unstable brown oil.

4.1.2.5 TBS和Boc官能团存在下用BF₃-HOAc脱去三苯甲基示例

Pickersgill, I, Fraser; Rapoport, Henry; J. Org. Chem., 2000, 65(14), 4048-4057

To a solution of 32 (2.67 g, 3.98 mmol) in CH₂Cl₂(27 mL) cooled to 0 °C were added glacial acetic acid (6.7 mL)and BF₃.Et₂O (0.529 mL, 4.17 mmol) dropwise, and the mixture wasstirred at 0 °C for 2 h.Cold (0 °C) 1 M NaOH (160 mL) was added and the mixturepartioned between CHCl₃/IPA (320 mL, 3/1) and cold (0 °C) 1 M NaOH (66 mL), followed by extraction with further portions ofCHCl₃/IPA (2 x 160 mL, 3/1). The combined organic phase wasdried, filtered, and evaporated to a residue which was chromatographed (CH₂Cl₂/MeOH,19/1 to 9/1) to give 33 (1.50 g,88%) as a colorless oil: [α]²²_D= +3.1 (c = 1.0,CHCl₃).

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