對甲苯磺酰胺由胺和對甲苯磺酰氯在吡啶或水溶性堿存在下制得的，它是最穩(wěn)定的氨基保護(hù)基之一，對堿性水解和催化還原穩(wěn)定。堿性較弱的胺如吡咯和吲哚形成的對甲苯磺酰胺比堿性更強(qiáng)的烷基胺所形成的對甲苯磺酰胺更易去保護(hù)，可以通過堿性水解去保護(hù)，而后者通過堿性水解去保護(hù)是不可能的。對甲苯磺酰胺一個(gè)很有吸引力的性質(zhì)是這些衍生物的酰胺或氨基甲酸酯更容易形成結(jié)晶。除在早期作過α-氨基的保護(hù)基外，一般都是用作堿性氨基酸的側(cè)鏈保護(hù)基。

Tos-氨基酸能夠通過酰氯、疊氮、DCC和四乙基焦亞磷酸等方法進(jìn)行接肽，但混合酸酐法一般不能采用。這是因?yàn)門os基得強(qiáng)烈吸電子效應(yīng)使得被酰化的氨基上的氫原子容易離去，而在用混合酸酐法接肽時(shí)會產(chǎn)生N，N-雙取代等副反應(yīng)使產(chǎn)率很低。同樣，Tos-氨基酸的酰氯在NaOH等強(qiáng)堿作用下很不穩(wěn)定，會發(fā)生分解生成Tos-NH2、醛和CO（見下式）[1]

1.A.F. Beecham., Chem. Ind.,(London)., 1955, 1120; J. Am. Chem. Soc., 1957,79, 3257

1對甲苯磺酰基的引入

對甲苯磺酰氯在NaOH、NaHCO3或其他有機(jī)堿存在下同氨基酸、吡咯和吲哚等反應(yīng)很容易得到良好產(chǎn)率的Tos-衍生物[1]

1. S. Sakakibara,T. Fujii., Bull. Chem. Soc. Jpn.,1969, 42, 1466

1.1對甲苯磺酰基的引入示例

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, and100 mL of dry THF areplaced in a 300-mL,round-bottomed flask, equipped with a pressure-equalizing dropping funnel, amagnetic stirring bar, and a nitrogen inlet. The dropping funnel is charged with a solution of18.9 g (99.1 mmol) of p-toluenesulfonyl chloride in 50 mL dry THF. The reactionmixture is cooled to 0°Cwith magnetic stirring, and the solution of p-toluenesulfonyl chloride is delivereddropwise over a 30-min period. The resulting cloudy solution is stirred for 60hr at ambient temperature. After this time period, the reaction mixture isdiluted with 50 mL ofsaturated sodium chloride solution and 50 mL of ethyl acetate, transferred toa 500-mL separatory funnel,mixed thoroughly, and the organic phase separated. The aqueous phase isextracted twice with 50 mLof ethyl acetate. The combined organic layers are dried (Na2SO4),filtered, concentrated under reduced pressure, and the resulting residuepurified by chromatography to give 22.43 g (61%) of compound 2 (Rf = 0.34, CHCl3/EtOAc, 1:1) as acolorless solid, mp 144–146°C.

2對甲苯磺酰基的脫去

Tos非常穩(wěn)定，它經(jīng)得起一般酸解(TFA和HCl等）、皂化、催化氫解等多種條件得處理比受影響，常用萘鈉[1]、Na/NH3(液) [2]和 Li/NH3(液) [3]處理脫去。HBr/苯酚[4]和Mg/MeOH 也是比較好的去保護(hù)方法[5]。值得注意的是，Na/NH3(液)的操作比較麻煩，并且會引起一些肽鍵的斷裂和肽鏈的破壞。另外，有時(shí)HF/MeCN回流也能脫去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, Petraet al., Chem. Europ. J., 2003, 9(23), 5899-5915; Calvisi, 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

2.1 Na/NH3脫除對甲苯磺酰基示例

A. Schrey; F.Osterkamp et al., Eur. J. Org. Chem., 1999, 11, 2977

To a two necked flask equippedwith a dry ice condenser was added compound1 (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 solutionuntil a blue color color persisted for 5 min. After stirring for 10 min, thereaction was quenched by adding dropwise glacial acetic acid (2 ml). The NH3was allowed to evaporate. The crude product was dried invacuo for 1 h to give compound2 (1.3 g, 89%)as a colorless oil.

2.2 Li/NH3脫除對甲苯磺酰基示例

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 mlof liquid NH3. The resulting dark blue solution was stirred for 1 hand then quenched with 1 ml of absolute ethanol. The ammonia was evaporated.The residue was diluted with saturated aqueous NaCl (30 ml), and extracted withCH2Cl2 (4 x 20 ml). The combined layers was dried and thesolvent evaporated to give compound 2 (0.4 g, 55%) as oil.

2.3 Na/萘脫除對甲苯磺酰基示例

Kaiser, Alexander; Balbi, Miriam et al., Tetrahedron: Asymmetry, 1999, 10(5), 1001-1014

To a solution ofcompound 1(0.78 g,1.83 mmol) in dry THF (20 ml) a solution of sodium naphthalenide [31 ml; prepared by stirring naphthalene (3.96 g,31.2 mmol) and small pieces of sodium (1.92 g, 83.8 mmol) in dry THF (120 ml) for 3 h at roomtemperature under nitrogen] was added over 10 min at -78°C. After 6.5 h at -78°C, water (5 ml) was added, and THF was removedunder reduced pressure. The mixture was diluted with water (10 ml) andextracted with EtOAc (3 x 30ml). The combined EtOAc layers were washed with brine (2 x 20 ml), dried and evaporated. Column chromatography (CH2Cl2:MeOH, 9:1) afforded compound 2(0.17 g, 39%) as a colorless oil.

2.4 HBr/苯酚脫除對甲苯磺酰基示例

Calvisi, Giuseppina; Dell-Uomo, Natalinaet al., Eur. J. Org. Chem., 2003, 23, 4501-4506

Around-bottom flask containing a mixture of compound 1 (600 mg, 1.94 mmol), phenol (547 mg, 5.82 mmol)and HBr (7.5 mL, 48%) was placed in an oil bath previously heated to 130 °C and refluxed for 18 hours. Thereaction mixture was then allowed to cool to room temperature, diluted withwater and extracted twice with EtOAc. The aqueous layer was evaporated undervacuum, the residue was taken up several times with CH3CN(evaporating under vacuum every time) until a solid residue, insoluble in CH3CN,was obtained. The solid was filtered and dried to give compound 2 (230 mg, 95%) as the dihydrobromidesalt.

2.5 Mg/MeOH脫除對甲苯磺酰基示例

Nenajdenko, Valentine G; Karpov, Alexei Set al., Tetrahedron: Asymmetry, 2001, 12(18), 2517-2528

To a suspension of Mg (0.45 g, 20 mmol) in MeOH (5 mL) was added a solutionof compound 1 (0.74 g, 2 mmol) in MeOH (10 mL). Theresulting suspension was sonicated for 1 h until consumption of the startingmaterial was complete. The reaction mixture was then diluted with aqueous NH4Cland extracted with ether (3 x 5 mL). The organic layer was dried over MgSO4and evaporated. To resulting oil ethanolic solution HCl (2 M, 0.5 mL) was added. Hydrochloride wasprecipitated, filtered and washed with ether to afford compound 2 HCl salt (0.46 g, 90%) as a white solid.

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