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1、目 录1. 简介22. 硅醚22.1 三甲基硅醚 (TMS-OR) 32.2 叔丁基二甲基硅醚 (TBDMS-OR) 42.3 叔丁基二苯基硅醚(TBDPS-OR) 43. 苄醚64. 取代苄醚75. 取代甲基醚86. 四氢吡喃醚97. 烯丙基醚101. 前言羟基广泛存在于许多在生理上和合成上有意义的化合物中，如核苷，碳水化合物、甾族化合物、大环内酯类化合物、聚醚、某些氨基酸的侧链。 。另外，羟基也是有机合成中一个很重要的官能基，其可转变为卤素、氨基、羰基、酸基等多种官能团。在化合物的氧化、酰基化、用卤代磷或卤化氢的卤化、脱水的反应或许多官能团的转化过程中，我们常常需要将羟基保护起来。 在含有
2、多官能团复杂分子的合成中，如何选择性保护羟基和脱保护往往是许多新化合物开发时的关键所在，如紫杉醇的全合成。羟基保护主要将其转变为相应的醚或酯，以醚更为常见。一般用于羟基保护醚主要有硅醚、甲基醚、烯丙基醚、苄基醚、烷氧甲基醚、烷巯基甲基醚、三甲基硅乙基甲基醚等等。羟基的酯保护一般用的不多，但在糖及核糖化学中较为多见。2. 羟基硅醚保护及脱除 硅醚是最常见的保护羟基的方法之一。随着硅原子上的取代基的不同，保护和去保护的反应活性均有较大的变化。当分子中有多官能团时，空间效应及电子效应是影响反应的主要因素。在进行选择性去保护反应时，硅原子周围的空间效应，以及被保护分子的结构环境均需考虑。例如，一般情况
3、下，在 TBDMS 基团存在时，断裂DEIPS( 二乙基异丙基硅基) 基团是较容易的，但实际得出的一些结果是相反的。在这些例子中，分子结构中空间阻碍是产生相反选择性的原因。电子效应的不同也会影响反应的选择性。对于两种空间结构相似的醇来说，电子云密度不同造成酸催化去保护速率不同，因此可以选择性去保护。这一点对酚基和烷基硅醚特别有效：烷基硅醚在酸中容易去保护，而酚基醚在碱性条件下更容易去保护。降低硅的碱性还可以用于改变 Lewis 酸催化反应的结果，并且有助于选择性去保护。在硅原子上引入吸电子取代基可以提高碱性条下水解反应的灵敏性，而对酸的敏感性降低。对大多数醚来说，在酸中的稳定性为 TMS (1
4、)EETHP。4.1 THP (2-四氢吡喃) 保护羟基THP 醚引入到一个手性分子的结果是形成了一个非对映体，因为在四氢吡喃环上新增了一个手性中心。 （有时它会使 NMR 谱的表达有点困难） 。尽管如此， 它仍是有机合成中一个非常有用的保护基团，它的成本低，易于分离，对大多数非质子酸试剂有一定的稳定性，易于被出去。通常，几乎任何酸性试剂或任何可以在原位产生酸的试剂都可被用来引入 THP 基团。4.1.1 THP (2-四氢吡喃)保护羟基示例( J.Org.Chem.1977,42,3772)t-BDPSiO HOCCC6H51 2t-BDPSiOTHPOCCC6H5DHP/PPTSTo a
5、solution of 1 (1.5 g, 3.5mmol) in CH2Cl2 (10 mL) at 22-24oC was added 3,4- dihydro-2H-pyran (0.479 mL, 0.442 g, 5.25mmol) and PPTs (20 mg, 0.08mmol). The solution was stirred at 22-24oC for 1 h and diluted with a 100-mL solution of (1:1) diethyl ether and ethyl acetate. The organic layer was separat
6、ed, washed with H2O (3 100mL), and the residue was chromatographed, eluting with hexane/ethyl acetate (20:1) to give the THP ether 2 as clear oil (1.75 g, 97%).4.1.2 THP (2-四氢吡喃)脱保护示例( J.Org.Chem.1977,42,3772)C OTHPCCC6H51 2OHCR C OHCCC6H5OHCRPPTS/EtOH/50oCTo an ethanol solution (30 mL) of THP ether
7、 1 (1.87 g, 5mmol) was added PPTS (20 mg, 0.08mmol) in one portion. The solution was refluxed for 1 h, cooled to 22-24oC, and diluted with a mixture of diethyl ether (100 mL) and H2O (200 mL). The organic layer was washed with H2O (2 100mL), dried over Na2SO4 and concentrated in vacuo. The residue w
8、as purified by chromatography on silica gel, eluting with hexane/ethyl acetate (3:1) to give 2 (1.36 g, 94%) as clear oil.4.2 MOM 保护羟基MOM 是一般是通过 MOMCl-DIEA 引入；其对酸还是较为稳定的，一般它的脱除需要在强酸条件下进行。4.2.1 MOM (CH3OCH2-OR)羟基保护示例(J. Org. Chem. 1995,60,7796)OPMBOHTBDPSO MOMCl,DIEA, CH2Cl2 OPMBMOMTBDPSO1 2To a stir
9、red solution of (1) (51.0 g, 99 mmol) in CH2Cl2 (1.0 L) at room temperature were successively added DIEA (51.5 mL, 0.297 mol) and MOMCl (15.0 mL, 0.198 mol) over a 10 min period. The solution was stirred 11 h at room temperature after which a saturated aqueous NH4Cl solution (200 mL) was added. The
10、aqueous phase was segregated, and the organic one was washed with water (100 mL), brine (100 mL0, dried with anhydrous MgSO4, filtered, and concentrated to give pure MOM ether (2) (55.3 g, 100%) (slightly yellowish oil).4.2.2 MOM 脱保护示例(ibid)OPMBOMOMTIPSO CO2CH3OOPMBOHTIPSO CO2CH3OHCl(gas)/iPrOH,5oC1
11、 2To a stirred solution (1) (1.00 g, 1.45 mmol) in dry isopropyl alcohol (10.0 mL) were added two drops (0.06 mL) of concentrated aqueous hydrochloric acid. The solution was stirred at 55oC for 10 h and although incomplete as indicated by TLC analysis, was allowed to cool to room temperature (prolon
12、ged reaction times tend to give substantial decomposition). A saturated aqueous NaHCO3 (20 mL) and diethyl ether (50 mL) were added to the mixture. The phase was separated and the aqueous layer was extracted with diethyl ether (5 50 mL). The combined organic layer was washed with brine (10 mL), drie
13、d over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography to give (2) (0.63 g, 65%). 4.3 EE（CH 3 CH2OCH3CH-OR）保护羟基EE 的性质和 THP 差的不是很多。4.3.1 EE（ CH3 CH2OCH3CH-OR）羟基保护示例 (J.Am.Chem.Soc. 1981,103,2427)OOHOHOOTBDMSH2CCHOEtTsOH OOEOHOOTBDMS1 2Selective reaction of th
14、e primary hydroxyl group in 1 with ethyl vinyl ether at 22oC by using pyridinium tosylate as catalyst in CH2C12 was followed by formation of the methanesulfonate ester at C-6, to produce 2.4.3.2 EE 脱保护示例 (J.Am.Chem.Soc. 1986,108,1035)CO2C2H5EO OHHOPTS1 2A solution of 19 mg (0.043 mmol) of ester 20 i
15、n 0.2 mL ether was treated at 0oC with 100 mL of a 1 M solution of LAH in ether. After 5 min the solution was quenched with water and was extracted with ether. The solvent was evaporated and the residue was dissolved in 0.5 mL of methanol containing a few crystals of PPTS. The solution was stirred at 25oC for 2 h. The methanol was evaporated and the residue was dissolved in ether. The combined organic extract was washed with saturated aqueous sodium bicarbonate and the aqueous phase was back extracted with ether. The ether extracts were combined, washed w
