有机合成后处理技巧（有机合成中的羟基保护方法有哪些）

有机合成后处理技巧（有机合成中的羟基保护方法有哪些）4.1.2 烯丙基脱保护示例(J.Chem.Soc. Perkins Trans 1 1980 738)A mixture of 1 (50 g) powdered NaOH (50 g) benzene (500 mL) and allyl bromide (12 mL) was heated under reflux and the progress of the reaction was followed by TLC (ether: petroleum 1:1). After 80 min. some starting material (Rf 0.15) remained and some diallyl derivatives present but the major product was the monoallyl derivatives (Rf 0.56)

羟基是一种常见的极性基团，化学式为-OH。羟基与水有某些相似的性质，羟基是典型的极性基团，与水可形成氢键。在无机化合物水溶液中以带负电荷的离子形式存在（OH-），称为氢氧根。羟基主要分为醇羟基，酚羟基等。

"羟"是化学家发明的字，以"氢"与"氧"二字各取一部份造出。读音则是"氢"的声母（qīng）加上"氧"的韵母及声调（yǎng）利用反切的方式合成一个字。因为j/q/x后面必须接i或ü，所以拼音作qiǎng。

羟基广泛存在于许多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团，其可转变为卤素、氨基、羰基、羧基等多种官能团。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合成时的关键所在。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。一般用于羟基保护的醚主要有硅醚、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。

4 其他保护基

4.1 烯丙基保护羟基

有关碳水化合物的文献中，烯丙醚用来保护醇是很常见的，原因在于烯丙醚通常可用各种方法形成糖苷。显然，烯丙醚不能与强的的亲电试剂共存，如溴、催化氢化的试剂。但它在中等强度的酸性条件（1N HCl，回流，10小时）下稳定。其易于生成，并在大量其它保护基存在下，有许多温和的脱保护方法。所以其总体上的稳定性，使得烯丙醚成为许多反应系列中的首选保护基。已有关于全氘代烯丙溴的合成及将它用作碳水化合物保护基方面的报道，全氘化合物的优点在于：烯丙基的NMR中的共振不再掩蔽其它可供鉴定的共振吸收峰，如糖苷的导头碳的吸收峰。

4.1.1 烯丙基保护羟基示例(J.Org.Chem.C 1969 2367)

A mixture of 1 (50 g) powdered NaOH (50 g) benzene (500 mL) and allyl bromide (12 mL) was heated under reflux and the progress of the reaction was followed by TLC (ether: petroleum 1:1). After 80 min. some starting material (Rf 0.15) remained and some diallyl derivatives present but the major product was the monoallyl derivatives (Rf 0.56) the benzene solution was washed with water dried (K2CO3) and evaporated. The syrupy product was chromatographed on alumina elution with benzene:ether removed the diallyl derivative (9 g) and elution with ether-methanol (25:1) gave the monoallyl derivatives (35 g ). Further elution with methanol gave unchanged starting material (8 g).

4.1.2 烯丙基脱保护示例(J.Chem.Soc. Perkins Trans 1 1980 738)

A solution of menthyl allyl ether (0.114 g 0.58 mmol) (prepared from menthol sodium hydride and allyl bromide) RhCl(PPh3)3 (0.037 g 0.040 mmol) and diazabicyclo[2 2 2]octane (0.013 g 0.120 mmol) (added to inhibit premature hydrolysis of the intermediate enol ether. Free propionaldehyde reacts with RhCl(PPh3)3 to form the catalytically much less active RhCl(PPh3)2CO.) in 10% aqueous ethanol was heated at reflux for 3 h. An aliquot was injected into 1 N HCl and after a few minutes was assayed by vpc analysis which showed only menthol and menthyl allyl ether in 93% and 7% yield respectively. Work up of a parallel reaction (by poured into water extracting with ether washing the ether with brine acidified to pH 2 drying over MgSO4 concentrated and separation on silica gel) gave menthol in 93% yield.

4.2 酰基保护

醇通过酯的保护一般用在糖化学中较为多见，一般主要通过乙酰基、苯甲酰基和特戊酰基等。乙酰基保护也常常用于天然产物结构鉴定中羟基衍生化。一般上乙酰基方法较多，其中用乙酸酐在吡啶中引入乙酰基最为常用，由于该方法不能乙酰化位阻较大的叔醇，要想在叔醇引入乙酰基需要加入酰化催化剂（DMAP 4-PPY）等，有时对位阻特别大的即使加入酰化催化剂（DMAP 4-PPY）也无效时，可以考虑通过Lewis酸催化，Procopiou P. A.等人报道利用TMSOTf催化位阻较大的叔醇的乙酰化，效果要比Ac2O/DMAP体系更好（J. Org. Chem. 1998 2342）。苯甲酰化的常用方法是BzCl或Bz2O/吡啶。特戊酰化的常用方法是PvCl /吡啶 0-75℃。这些酰基化对伯醇选择性要大于仲醇，选择性特戊酰基>苯甲酰>乙酰基；有时特戊酰基可化学选择性的上在伯醇上。

4.2.1乙酰化保护羟基示例 (DMAP: J. Org. Chem. 1993 3791)

Compound 1 (1.38 g 10 mmol) and Ac2O (0.95 mL 10 mmol) in CH2Cl2 (30 mL) were treated with Et3N (2 mL 10 mmol) and DMAP (122 mg 1 mmol) at 20oC and the mixture was stirred for 4 d. The mixture was diluted with CH2Cl2 and washed with 2M HCl NaHCO3 H2O dried and chromatographed on silica gel eluting with ethyl acetate-cyclohexane (1:3 1:1 to give the diactate (2) (500 mg 22%) the O-aryl acetate (3) (705 mg 39%) and the O-alkyl acetate (4) (54 mg 3%).

4.2.2 Lewis酸催化乙酰化保护叔羟基示例 (TMSOTf，Ac2O J. Org. Chem. 1998 2342)

Compound 1 (1.38 g 10 mmol) in CH2Cl2 (10 mL) and Ac2O (0.95 mL 10 mmol) were treated with TMSOTf in CH2Cl2 (1M 0.25 mL ) at 20oC. The reaction mixture was checked by HPLC after 1 h and indicated a mixture (22:48:30). After stirring for 21 h the starting material was consumed and the mixture of product was 88:12. After stirring for a total of 3.5 d the ratio improved to 93:7. The mixture was washed with water and brine dried and evaporated to give the O-alkyl acetate (4) (1.577 mg 88%).

4.2.3 乙酸酯脱保护示例 (J.Am.Chem.Soc. 1972 94 8613)

A mixture of 1 (1.59 g 6.0 mmol) and K2CO3 (2 g 14.3 mmol) in MeOH (5 mL) and water (3 mL) was stirred at room temperature for 12 h. The mixture was concentrated in vacuo to a volume of 3.5 mL and extracted with CH2Cl2 (25 mL 3). The extract was dried over MgSO4 and concentrated in vacuo to afford 2 1.13 g (85%).

4.2.4 苯甲酰化保护羟基示例( J.Org.Chem. 1981 46 5252)

To a solution of 1 (0.94 g. 2.9 mmol) in pyridine (20 ml) benzoyl chloride (1.26 g 9 mmole) was added with stirring and ice-cooling. Stirring was continued overnight at room temperature. The mixture was poured into ice-water and extracted with benzene. The benzene extract was washed with water dried and evaporated to leave a faint yellow caramel (l.62 g) which was triturated with i-PrOH to form crystals. These were recrystallized from i-PrOH to give colourless plates m.p. 106-107.5oC yield 1.31 g (85%).

4.2.5 苯甲酸酯脱保示例( J.Org.Chem. 1981 46 5252)

Dibenzoate 1 (500 mg 09 mmol) was added to a solution of NaOH (250 mg 62 mmol) in MeOH (35 mL) and the resulting mixture was stirred at room temp for 50 min. After evaporation of MeOH in vacuo and addition of water the solid separated was extracted with benzene-AcOEt. The organic extract was washed with water dried and the solvent was removed. The residue was chromatographed on silica gel to give a colorless caramel 2 yield 360 mg (90%).

4.2.6 特戊酰基保护羟基示例(J.Am.Chem.Soc. 1980 102 7962)

The triol 1 (3.24 g 20 mmol) is dissolved in pyridine (20 mL) and dry didhloromethane (20 mL) is added. To the cold (0oC) and stirred solution under argon is added dropwise over a period of 30 min. pivaloyl chloride (2.48 mL 20 mmol). The cooling is then removed and the mixture is stirred at room temperature for 14h. Concentrated followed by azeotropic removal of pyridine (toluene) gives a syrup which is purified by flash column chromatography on silica gel (50% ether in petroleum ether) yield 2 as a colorless oil yield 4.43g (90%).

4.2.7 特戊酸酯脱保护示例(J.Am.Chem.Soc. 1990 112 3693)

A solution of 136 mg (0.3 mmol) of 1 in 20 mL of MeOH was hydrogenated at atmospheric pressure over 40 mg of 5% Pd/BaCO3 for 24 h at room temperature. The mixture was filtered using a Celite pad and the filtrate was evaporated. The resulting colorless glass was dissolved in 10 mL of MeOH and stirred with 49 mg (0.9 mmol) of NaOMe for 20 h at room temperature during which time white crystals separated. These were filtered and washed well with MeOH to give 66 mg of 2. The filtrate was neutralized with HOAc and concentrated and the residue was purified by preparative TLC (developed using the upper phase of EtOAc/n-PrOH/H2O 4:1:2). Recrystallization of this material from MeOH/95% EtOH gave an additional 18 mg for a total yield of 84 mg (80%) of 2.

合成过程中羟基的的保护多种多样，同一化合物的不同羟基选用不同的保护基，从而实现复杂的合成的例子比比皆是。我们在熟练掌握以上的一些保护和脱保护的方法后，要灵活运用，从而实现化繁为简，事半功倍的效果。

如果您喜欢这篇文章，记得点赞收藏转发评论一键四连哦！！！