of starting material. AcOH (1 ml) was added carefully and when the foaming subsided, the flask was stoppered and heated to 80°C for 2 h. The crude reaction mixture was then eluted onto a Dowex 50 (H+) column (2.7 x 10 cm), washed with H2O (150 ml), then eluted with 1 M NH4OH (200 ml). Ninhydrin-active fractions were collected and pooled for freeze drying, and thus afforded compound 2 (0.2 g, 89%) as an ammonium salt.
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3.2 对甲苯磺酰基（Tos）
对甲苯磺酰胺由胺和对甲苯磺酰氯在吡啶或水溶性碱存在下制得的，它是最稳定的氨基保护基之一，对碱性水解和催化还原稳定。碱性较弱的胺如吡咯和吲哚形成的对甲苯磺酰胺比碱性更强的烷基胺所形成的对甲苯磺酰胺更易去保护，可以通过碱性水解去保护，而后者通过碱性水解去保护是不可能的。对甲苯磺酰胺一个很有吸引力的性质是这些衍生物的酰胺或氨基甲酸酯更容易形成结晶。除在早期作过α-氨基的保护基外，一般都是用作碱性氨基酸的侧链保护基。
Tos-氨基酸能够通过酰氯、叠氮、DCC和四乙基焦亚磷酸等方法进行接肽，但混合酸酐法一般不能采用。这是因为Tos基得强烈吸电子效应使得被酰化的氨基上的氢原子容易离去，而在用混合酸酐法接肽时会产生N，N-双取代等副反应使产率很低。同样，Tos-氨基酸的酰氯在NaOH等强碱作用下很不稳定，会发生分解生成Tos-NH2、醛和CO（见下式）[1]
RClOCH2ONHTosNaOHClOCRN-TosNa++H2ORNTos+CO+NaClTos-NH2+RCHO+CO+NaCl
1. A. F. Beecham., Chem. Ind., (London)., 1955, 1120; J. Am. Chem. Soc., 1957, 79, 3257
3.2.1 对甲苯磺酰基的引入
对甲苯磺酰氯在NaOH、NaHCO3或其他有机碱存在下同氨基酸、吡咯和吲哚等反应很容易得到良好产率的Tos-衍生物[1]
1. S. Sakakibara, T. Fujii., Bull. Chem. Soc. Jpn., 1969, 42, 1466
3.2.1.1对甲苯磺酰基的引入示例
ONHNH21Et3N, THFHCOOMeOTsClNNHTs2COOMe
Arthur G. Schultz and Carlos W. Alva., Org. Syn., 73, 174
22.9 g (90 mmol) of compound 1 , 13.66 g (135 mmol) of triethylamine, and 100 mL of dry THF are
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placed in a 300-mL, round-bottomed flask, equipped with a pressure-equalizing dropping funnel, a magnetic stirring bar, and a nitrogen inlet. The dropping funnel is charged with a solution of
18.9 g (99.1 mmol) of p-toluenesulfonyl chloride in 50 mL dry THF. The reaction mixture is cooled
to 0°C with magnetic stirring, and the solution of p-toluenesulfonyl chloride is delivered dropwise over a 30-min period. The resulting cloudy solution is stirred for 60 hr at ambient temperature. After this time period, the reaction mixture is diluted with 50 mL of saturated
sodium chloride solution and 50 mL of ethyl acetate, transferred to a 500-mL separatory funnel,
mixed thoroughly, and the organic phase separated. The aqueous phase is extracted twice with
50 mL of ethyl acetate. The combined organic layers are dried (Na2SO4), filtered, concentrated
under reduced pressure, and the resulting residue purified by chromatography to give 22.43 g (61%) of compound 2 (Rf = 0.34, CHCl3/EtOAc, 1:1) as a colorless solid, mp 144–146°C.
3.2.2 对甲苯磺酰基的脱去
Tos非常稳定，它经得起一般酸解(TFA和HCl等）、皂化、催化氢解等多种条件得处理比受影响，常用萘钠[1]、Na/NH3(液) [2] 和 Li/NH3(液) [3]处理脱去。HBr/苯酚[4]和Mg/MeOH 也是比较好的去保护方法[5]。值得注意的是，Na/NH3(液)的操作比较麻烦，并且会引起一些肽键的断裂和肽链的破坏。另外，有时HF/MeCN回流也能脱去Tos基
[6]
。
1. Masuda, Yui; Mori, Kenji et al., Biosci. Biotechnol. Biochem., 2002, 66(7), 1531-1537; Kaiser, Alexander; Balbi, Miriam et al., Tetrahedron: Asymmetry, 1999, 10(5), 1001-1014; Takikawa, Hirosato; Muto, Shiu-etsu et al., Tetrahedron, 1998, 54(13), 3141-3150; Sugimura, Hideyuki; Miura, Masayuki et al., Tetrahedron: Asymmetry, 1997, 8(24), 4089-4100
2. J. Kovacs, U. R. Ghatak., Chem. Ind. (London)., 1963, 913; Dolence, E. Kurt; Roylance, Jason B et al., Tetrahedron: Asymmetry, 2004, 15(20), 3307-3322; Amat, Mercedes; Seffar, Fatima et al., Synthesis, 2001, 2, 267-275; Hoye, Thomas R; Chen, Minzhang et al., Tetrahedron Lett., 1996, 37(18), 3099-3100; Hoye, Thomas R; Chen, Minzhang et al., J. Org. Chem., 1999, 64(19), 7184-7201
3. Burgess, Kevin; Liu, Lee T et al., J. Org. Chem., 1993, 58(17), 4758-4763
4. Kotek, Jan; Lebduskova, Petra et al., Chem. Europ. J., 2003, 9(23), 5899-5915; Calvisi,
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Giuseppina; Dell-Uomo, Natalina et al., Eur. J. Org. Chem., 2003, 23, 4501-4506; Currie, Gordon S; Drew, Micheal G. B et al., J. Chem. Soc. Perkin Trans. 1, 2000, 17, 2982-2990; Davis, Franklin A; Srirajan, Vaidyanathan et al., J. Org. Chem., 2000, 65(10), 3248-3251; Davis, Franklin A; Liu, Hu et al., J. Org. Chem., 1999, 64(20), 7559-7567; Drury, William J; Ferraris, Dana et al., J. Am. Chem. Soc., 1998, 120(42), 11006-11007
5. Y. Yokoyama, T. Matsumoto et al., J. Org. Chem., 1995, 60, 1486; B. Nyasse, L. Grehn et al., J. Chem. Soc. Chem. Commun., 1997, 1017; Nenajdenko, Valentine G; Karpov, Alexei S et al., Tetrahedron: Asymmetry, 2001, 12(18), 2517-2528
6. Takikawa, Hirosato; Maseda, Takeshi et al., Tetrahedron Lett., 1995, 36(42), 7689-7692
3.1.2.1 Na/NH3脱除对甲苯磺酰基示例
TosHNH1 Na/NH3OHOHH2NH2OHOH
A. Schrey; F. Osterkamp et al., Eur. J. Org. Chem., 1999, 11, 2977
To a two necked flask equipped with a dry ice condenser was added compound 1 (3.20 g, 10.1 mmol) in THF (15 ml) and ammonia gas to condense about 25 ml of liquid. Small pieces of sodium (552 mg, 24.2 mmol) were added to the stirred solution until a blue color color persisted for 5 min. After stirring for 10 min, the reaction was quenched by adding dropwise glacial acetic acid (2 ml). The NH3 was allowed to evaporate. The crude product was dried in vacuo for 1 h to give compound 2 (1.3 g, 89%) as a colorless oil.
Li/NH3脱除对甲苯磺酰基示例
NHTosOH12Li/NH3NH2OH
Burgess, Kevin; Liu, Lee T et al., J. Org. Chem., 1993, 58(17), 4758-4763
Lithium metal was added to a solution of compound 1 (1.5 g, 5.01 mmol) in 5 ml of THF and 200 ml of liquid NH3. The resulting dark blue solution was stirred for 1 h and then quenched with 1 ml of absolute ethanol. The ammonia was evaporated. The residue was diluted with saturated aqueous NaCl (30 ml), and extracted with CH2Cl2 (4 x 20 ml). The combined layers was dried and the solvent evaporated to give compound 2 (0.4 g, 55%) as oil.
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