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]
1.A.F. Beecham., Chem. Ind.,(London)., 1955, 1120; J. Am. Chem. Soc., 1957,79, 3257
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
1.1对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., , 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脱除对甲苯磺酰基示例
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脱除对甲苯磺酰基示例
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/萘脱除对甲苯磺酰基示例
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/苯酚脱除对甲苯磺酰基示例
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脱除对甲苯磺酰基示例
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.
本文由
http://pf-e.cn 创作,除注明转载/出处外,均为本站原创,转载前请务必署名
最后编辑时间为: 2020-05-07 23:39 Thursday
官方招商
顶部按钮联系主管注册