羟基的保护-20060120

经典化学合成反应标准操作
羟基的保护
目录
1.简介 (2)
2.硅醚 (2)
2.1三甲基硅醚(T M S-O R) (3)
2.2叔丁基二甲基硅醚(T B D M S-O R) (4)
2.3叔丁基二苯基硅醚(T B D P S-O R) (4)
3.苄醚 (6)
4.取代苄醚 (7)
5.取代甲基醚 (8)
6.四氢吡喃醚 (9)
7.烯丙基醚 (10)
1.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)<TES (64)<TBDMS (20,000)<TIPS (700,000)<TBDPS (5,000,000)；在碱中稳定性为TMS (1)<TES (10-100)<TBDMS~TBDPS (20,000)< TIPS (100,000)。

一般而言，对于没有什么位阻的伯醇和仲醇，尽量不要选用TMS作为保护基团，因为得到的产物一般在硅胶这样弱的酸性条件下也会被裂解掉。

任何羟基硅醚的都可以通过四烷基氟化胺如TBAF脱除，其主要硅原子对氟原子的亲和性远远大于硅-氧之间的亲和性。

在用TBAF裂解硅醚后，分解产生的四丁铵离子有时通过柱层析或HPLC很难除干净，而季铵盐的质谱丰度(Bu4N+: 242)又特别的强有
时会干扰质谱，因此这时需要使用四甲基氟化铵或四乙基氟化铵来脱除。

使用硅醚保护的另一个好处是可以在分子中游离伯胺或仲胺基的存在下，对羟基进行保护，其主要由于硅-氮键的结合远比硅-氧键来的弱，硅原子优先与羟基上的氧原子结合，这正是与其他保护基不同之处。

顺便提一句，一般而言，决大部分的硅-氮键的结合是不稳定的，其很容易被水解掉。

2.1 三甲基硅醚的保护 (TMS-OR)
许多硅基化试剂均可用于在各种醇中引入三甲基硅基。

一般来说，空间位阻较小的醇最容易硅基化，但同时在酸或碱中也非常不稳定易水解,三甲基硅基化广泛用于多官能团化合物，生成的衍生物具有较高的挥发度而利于其相色谱和质谱分析。

2.1.1 三甲基硅醚羟基保护示例 (J. Org.Chem. 1996, 61, 2065)
1
2
HO
TMSO
Me
Compound 1 (3.00g, 4.286mmol) was dissolved in dry DMF (17 mL). To this solution at 0o C was added imidazole (874.3 mg, 12.86mmol), followed by TMSCl (1.63 mL, 12.86 mmol). After stirring at 0o C for 1.5 h, the reaction mixture was diluted with EtOAc (300 mL) and washed with water (3 20 mL) and then brine (30 mL). The organic layer was dried and concentrated in vacuo . The resulting material was then dissolved in dry DMF (20 mL) and treated at 0o C with imidazole (816 mg, 12.00 mmol), followed by chlorodimethylsilane (1.135g, 12.00mmol). The reaction mixture was stirred for 1h at 0o C and then diluted with EtOAc (200mL). The organic layer was washed with water and brine. Upon silica gel chromatography (10% ethyl acetate in hexane), 3.197 g (90%) of the desired product 2 was obtained.
Cleavage (J. Org.Chem. 1996, 61, 2065)
Hydrolysis was carried out under aprotic condition-anhydrous tetrabutylammonium fluoride in THF solution.
2.2 t-Butyldimethylsilyl ether (TBDMS-OR)
在化学合成中，采用硅基化进行羟基保护生成叔丁基甲基硅基醚是应用较多的方法之一。

一般来说，在分子中羟基位阻不大时主要通过TBSCl 对羟基进行保护。

但当羟基位阻较大时则采用较强的硅醚化试剂TBSOTf 来实现。

生成的叔丁基二甲基醚在多种有机反应中是相当稳定的，在一定条件下去保护时一般不会影响其他官能团。

它在碱性水解时的稳定性约为三甲基硅醚的104倍。

它对碱稳定。

相对来说对酸敏感些。

TBS 醚的生成和断裂的难易取决于空间因素，因此常常用于对多官能团，位阻不同的分子进行选择性保护。

在伯、仲醇中，TBS 基相对来说较易于与伯醇反应。

TBS 醚的断裂除了常用的四烷基氟化胺外，许多情况下也可用酸来断。

当分子内没有对强酸敏感的官能基存在时，可用 HCl-MeOH, HCl-Dioxane 体系去除TBS ，若有对强酸敏感的官能基存在时，则可选用AcOH-THF 体系去除。

2.2.1 通过TBSCl 进行羟基的叔丁基二甲基硅醚保护示例 (J. Am. Chem. Soc. 1972, 94, 6190)
O
CH 2OBn
HO
O O
CH 2OBn
TBDMSO
O
1
2
The hydroxyl lactone 1, upon treatment with TBDMSCl (1.2 equiv) and imidazole (2.5 equiv.) in DMF (2 mL/g of 1) at 35o C for 10 h, produced the silyl ether-lactone 2 in 96% yield.
2.2.2 通过TBSOTf 进行羟基的叔丁基二甲基硅醚保护示例(.Chem. 1987, 52, 622)
3
1
2
To an ice-cold solution of 4.8 g of pyridine (2.0 equiv) and 4.20 g of 1 in 30 mL of dry acetonitrile was added slowly 9.6 g of tert-butyldimethylsilyl triflate (36.2 mmol, 1.2 equiv). The reaction mixture was stirred for 5 h at room temperature and then poured into 200 mL of saturated sodium bicarbonate solution at 0o C. The solution was extracted thoroughly with hexane, and the organic extracts were dried over anhydrous potassium carbonate and filtered. Removal of the solvent under reduced pressure followed by distillation of the residue gave
6.29 g (82% yield).
2.2.3 通过TBAF 脱TBDPS 示例 (Can. J. Chem. 1975, 53, 2975)
O
THPO
C C C 6H 5
Bu 4N +F -/THF
1
2
HO
THPO
C C C 6H 5
Si Ph Ph
To a solution of THP ether 1 (1.7 g, 3.3 mmol) in THF (10 mL) was added a 1 M solution of tetrabutylammonium fluoride in THF (5 mL, 5 mmol) at 22-24o C. The solution was stirred for 2 h and diluted with 100 mL (1:1) of Et 2O/EtOAc solution. The organic layer was separated and washed with H 2O (3 ⨯ 100 mL). The water extract was washed with 2:1 Et 2O/EtOAc solution (2 ⨯ 50 mL), and the
organic layers were combined and dried over MgSO 4. The solvent was evaporated in vacuo , and the residue was chromatographed over silica gel using (5:1) hexanes/ethyl acetate solution to give 2 (0.75 g, 82%).
2.2.4 通过AcOH-THF 脱
TBS 示例(Tetrahedron Lett. 1988, 29, 6331)
1
2AcOh/H 2O/THF
Selective removal of one of the TBDMS groups of 1 was accomplished by treatment with acetic acid-water-THF (13:7:3) (30°C, 15h) to give the monohydroxy compound 2 in 79% yield.
2.3 t-Butyldiphenylsilyl ether (TBDPS-OR)
在酸性水解条件下TBDPS 保护基比TBDMS 更加稳定（约100倍），而TBDPS 保护基对碱的稳定性比TBDMS 要差。

另外，由于该保护基的分子量较大，容易使底物固化而易于分离。

TBDPS 保护基对许多与TBDMS 保护基不相容的试剂显出比TBDMS 基团更好的稳定性。

TBDMS 基团在酸性条件下不易迁移。

TBDPS 醚对K 2CO 3 /CH 3OH ，对9M 氨水、60℃、2h ；对MeONa （cat.）/CH 3OH 、25℃、24h 均稳定。

该醚对80%乙酸稳定，后者可用于脱除醚中TBDMS ，三苯甲基，四氢吡喃保护基也对HBr /AcOH ，12℃，2min ；对25%~75%甲酸，25℃，2h~6h ；以及50%三氟乙酸，25℃，15min
稳定。

2.3.1 通过TBDPSCl 进行羟基的叔丁基二甲基硅醚保护示例(. Chem , 1992, 57, 1722)
i-Pr NEt/t-BDPSiCl/CH Cl OH
t-BDPSiO
1
2
HO
OH
To a solution of 1,4-butanediol (5 g, 55 mmol) in CH 2Cl 2 (10 mL) containing i-Pr 2NEt (10 mL) was added t-BDPSiCl (5 mL, 18 mmol) dropwise under N 2 at 22-24o C. The solution was stirred at 22-24o C for 2 h, concentrated in vacuo and chromatographed, eluting with hexanes/ethyl acetate (10:1) to 2 (clear oil, 5.6 g, 95%).
2.4 三异丙基硅醚保护 (TIPS-OR)
酸性水解时，有较大体积的TIPS 醚比叔丁基二甲基硅醚要更稳定些。

但稳定性比叔丁基二苯基硅基差。

TIPS 基碱性水解时比TBDMS 基或TBDPS 基稳定。

相对于仲羟基，TIPS 基对伯羟基有更好的选择性。

2.4.1通过TIPSCl 进行羟基的三异丙基硅醚保护示例(J. Org. Chem. 1995, 60, 7796)
3
3
22
1
2
To a stirred solution of (1)(1.5 g) in CH 2Cl 2 (53 mL) cooled to 0o C were successively added 2,6-lutidine (6.2 mL, 53.3 mmol) and triisopropylsilyl triflate (7.90 mL, 29.5mmol). The mixture was allowed to warm to room temperature (30 min). Then excess triflate was consumed by addition of methanol (10 mL) and a saturated aqueous NH 4Cl solution (60 mL). The phase was separated and the aqueous layer was extracted with CH 2Cl 2 (4 ⨯ 50 Ml). The combined organic phases were washed with a saturated NaHCO 3 (100 mL) a, 1M NaHSO 4 (3 ⨯ 50 mL), and brine (50 mL), dried over Na 2SO 4, filtered, and concentrated. Purification by flash chromatography (10% ethyl acetate in hexane) afforded silyl ether (2) (6.90 g, 89%).
3.羟基苄醚保护及脱除
一般羟基的苄醚保护主要有苄基，对甲氧苄基及三苯甲基醚。

3.1苄基醚保护羟基(Bn-OR)
一般烷基上的羟基在用苄基醚保护时需要用强碱，但酚羟基的苄基醚保护一般只要用碳酸钾在乙腈或丙酮中回流即可，回流情况下，这类烷基化在乙腈中速度比丙酮中要快四倍左右，因此一般用乙腈做溶剂居多。

若反应速度慢可用DMF做溶剂，提高反应温度，或加NaI,KI催化反应。

苄基醚的裂解主要是通过催化加氢的方法，Pd是理想的催化剂，用Pt时会产生芳环上的氢化作用。

在含色氨酸的肽中氢解苏氨酸常导致色氨酸还原成2，3-二氢衍生物。

非芳性的胺可以使催化剂活性降低，阻碍O-脱苄；在氢化体系中加入Na2CO3可以防止苄基被裂解，但可使双键发生还原。

孤立烯烃有可能影响苄基醚键的裂解（H2，5% Pd-C，97%产率）。

一般而言选择性的大小取决于取代的类型及空间位阻的情况。

与酯共扼的三取代的烯烃存在时，苄基的水解也有相当好的选择性。

对甲氧苄基基团存在时，苄基的水解（Pd-C，EtOAc，室温，18小时）有非常好的选择性。

在反应体系中加入Pyridine 可使对甲氧苄基和苄基氢解产生区别。

苄基的氢解有溶剂的作用，如下列表：
Effect of solvent on the hydrogenlysis of benzyl ether
3.1.1烷基羟基的苄基醚保护示例(Bull. Chem. Soc. Jpn. 1987, 60, 1529)
12
Compound 1 (12.1 g) in DMF (200 mL) was treated with 60% NaH (1.32 g), benzyl bromide (6.44 g) and tetrabutylammonium iodide (0.11 g). The reaction mixture was stirred at room temperature for 1.5 h. The product was purified by chromatography on silica gel with toluene-ethanol (20:1) to give 2 (14.0 g, 99%).
3.1.2 酚羟基的苄基醚保护示例
1
2
O
OH
O
O
K 2CO 3/EtOH
To a solution of 1 (37.65 g, 277 mmol) in EtOH (135 mL) was added benzyl chloride (36.5 g, 289 mmol), KI (1.75 g, 10 mmol) and K 2CO 3 (24.6 g, 178 mmol) with stirring. The resulting mixture was refluxed for 5 h. The mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was added water (100 mL) and extracted with Et 2O (80 mL 3). The extract was washed with saturated NaHCO 3, water and brine successively. The organic layer was dried over Na 2SO 4 and concentrated in vacuo to give the crude product, which was distilled to afford 2 (49.1 g, 79%).
3.1.3苄基醚氢解脱保护示例(J. Am. Chem. Soc. 1971, 93, 1746)
10%Pd/C/H 34
Compound 3 (105 mg) was hydrogenated in ethanol (10 mL) containing 1M hydrochloric acid (0.5 mL) in the presence of 10% palladium on charcoal (50 mg) in an initial hydrogen pressure of 3.4 MPa overnight. The product was purified by chromatography on silica gel with toluene-ethanol (3:1) to give 4 (90 mg, quant.)
3.2对甲氧基苄基醚保护羟基 (PMB-OR)
各种甲氧基苄醚已经合成得到并被用作保护基。

实际上甲氧基取代的苄基醚较未取代的苄基醚更容易通过氧化去保护。

下表给出了用二氯二氰苯醌去保护时的相对速率。

O
(OMe)n
CH 2Cl 2,H 2O (10:1), 20o C
OH
OHC
(OMe)n
ii
i
iii
Cleavage of MPM, DMPM, and TMPM ethers with DDQ in CH 2Cl 2/H 2O at 20o C
一般而言，对甲氧基苄醚在合成中更为常用，羟基上对甲氧基苄基的方法和苄基类似，但脱除除了氢解的方法外，还可以氧化除去。

3.2.1对甲氧基苄基醚保护示例(Tetrahedron Lett. 1988, 29, 2459)
O
Bn
O
Bn
NaH, DMF
OMe
ClH 2C
To a stirred suspension of NaH (26 mg 1.09 mmol) in DMSO (1 mL) was added dropwise a THF solution (3 mL) of 1 (250 mg, 0.78 mmol) under Ar. After 45 min. at room temperature MPM chloride (158 mg, 1.01mmol) was added, and the stirring was continued for 3 h. the mixture was poured into sat. NH 4Cl aq. And then extracted with ether. The extract was washed with sat. NaCl aq., dried over MgSO 4, and concentrated in vacuo to leave an oil, which was chromatographed on a short silica gel column elution with EtOAc-n-hexane (1:1) gave a colorless oil of 2 296 mg, 86%.
3.2.2 在苄氧基存在下选择性脱去对甲氧基苄基示例(Tetrahedron Lett. 1988, 29, 2459)
O
Bn
O
Bn
2
CH 2Cl 2-H 2O
To a stirred solution of 2 (92 mg, 0.286 mmol) in CH 2Cl 2 (2.9 mL) and water (0.17 mL) was added DDQ (97 mg, 0.427 mmol) at room temp. After 2.5 h precipitated DDQH was removed by decantation and washed with a small amount of CH 2Cl 2. The combined CH 2Cl 2 solution was washed with sat. NaHCO 3 aq. And sat. NaCl aq. And dried over Na 2SO 4. Evaporated of the solvent in vacuo gave an oil, which was chromatographed on a silica gel column with EtOAc-n-hexane (1:1) as eluant gave a colorless solid of 1 43.8 mg, 84%.
4. 烷氧基甲基醚或烷氧基取代甲基醚
烷氧基甲基醚或烷氧基取代甲基醚在羟基保护中也是较为多用的一类，常用的有THP (2-四氢吡喃)，MOM （甲氧基甲机基），EE （2-乙氧基乙基），这类保护基都对酸不稳定，因此一般都是脱保护。

它们对酸的稳定性是MOM>EE>THP 。

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(.Chem.1977,42,3772)
t-BDPSiO
HO C C C 6H 5
1
2
t-BDPSiO
THPO C C C 6H 5
To a solution of 1 (1.5 g, 3.5mmol) in CH 2Cl 2 (10 mL) at 22-24o C 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 22-24o C for 1 h and diluted with a 100-mL solution of (1:1) diethyl ether and
ethyl acetate. The organic layer was separated, washed with H 2O (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(.Chem.1977,42,3772)
C
OTHP
C C C 6H 51
2
OH C R C
OH
C C C 6H 5OH
C R PPTS/EtOH/50o C
To an ethanol solution (30 mL) of THP ether 1 (1.87 g, 5mmol) was added PPTS (20 mg, 0.08mmol) in one portion. The solution was refluxed for 1 h, cooled to 22-24o C, and diluted with a mixture of diethyl ether (100 mL) and H 2O (200 mL). The organic layer was washed with H 2O (2 ⨯ 100mL), dried over Na 2SO 4 and concentrated in vacuo . The residue was 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 (CH 3OCH 2-OR)羟基保护示例(J. Org. Chem. 1995,60,7796)
OPMB
OH
TBDPSO
OPMB
MOM
TBDPSO
1
2
To a stirred solution of (1) (51.0 g, 99 mmol) in CH 2Cl 2 (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 NH 4Cl solution (200 mL) was added. The 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)
2CH3
2CH3 o
12
To 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 55o C for 10 h and although incomplete as indicated by TLC analysis, was allowed to cool to room temperature (prolonged 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), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography to give (2) (0.63 g, 65%).
4.3 EE（CH3 CH2OCH3CH-OR）保护羟基
EE的性质和THP差的不是很多。

4.3.1EE（CH3 CH2OCH3CH-OR）羟基保护示例(J.Am.Chem.Soc. 1981,103,2427)
2C
TsOH
12
Selective reaction of the primary hydroxyl group in 1 with ethyl vinyl ether at –22o C by using pyridinium tosylate as catalyst in CH2C12 was followed by formation of the methanesulfonate ester at C-6, to produce 2.
4.3.2EE脱保护示例(J.Am.Chem.Soc. 1986,108
,1035)
PPTS
2
A solution of 19 mg (0.043 mmol) of ester 20in 0.2 mL ether was treated at 0o C 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 25o C 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 with brine, dried (Na 2SO 4,), and concentrated. The solid product was purified by HPLC (p-Porasil) to furnish 13 mg (90% overall) of desepoxyasperdiol as an oil.
4.4 SEM-Cl(TMSCH 2CH 2OCH 2-)保护羟基
SEM-作为羟基的保护基，其主要特点为最后脱保护可以通过四烷基氟化胺来脱去。

SEM 醚对分解四氢吡喃基(THP) 和叔丁基二甲基硅醚（TBS ）的酸性条件（AcOH-H2O, THF, 45o C, 7小时）是稳定的。

4.4.1 SEM-Cl(TMSCH 2CH 2OCH 2-)保护羟基示例(TL , 1980,3343)
R
OH +
TMSOCH 2CH 2OCH 2Cl
DIEA,CH Cl RO
O TMS
1
2
Exposure of an alcohol 1 in CH 2Cl 2 (ca, 2M) under an inert atmosphere containing 4-5 eq. of DIEA, to SEMCl (ca, 3 eq) at 25-40o C,affords the SEM ether in high yield.
4.4.2 SEM 保护基脱保护示例(ibid)
RO
O TMS
2
ROH +
CH 2O
+
H 2C CH 2
+
Me 3SiF
1
Bu 4NF
Removed of the SEM can be accomplished via reaction with Bu 4NF (at concentration > 2M) in dry THF at 45o C. Standard extractive workup followed by rough SiO 2 filtration give the desired product.
5. 其他保护基 5.1 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。

易于生成，在大量其它保护基存在下有许多温和的脱保护方法，及其总体上的稳定性，使得烯丙醚成为许多反应系列中的主干。

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。

5.1.1 烯丙基保护羟基示例(.Chem.C 1969, 2367)
BnO
OBn
OBn
OBn OH
HO BnO
OBn
OBn
OBn OH
AllylO
12
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).
5.1.2 烯丙基脱保护示例(J.Chem.Soc. Perkins Trans 1, 1980,738)
ROCH
2CH=CH2ROCH=CHCH3ROH + CH3CH2CHO
123
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)3to 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.
5.2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。

5.2.1乙酰化保护羟基示例(DMAP: J. Org. Chem.1993, 3791)
HO
2
AcO
OH
AcO
OAc
HO
++
1234
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 20o C, and the mixture was stirred for 4 d. The mixture was diluted with CH2Cl2and 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%).
5.2.2Lewis酸催化乙酰化保护叔羟基示例(TMSOTf，Ac2O, J. Org. Chem.1998, 2342)
HO
Ac O/TMSOTf OAc
AcO
OH
AcO
OAc
HO
++
1234
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 20o C. 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%).
5.2.3 苯甲酰化保护羟基示例( .Chem. 1981, 46, 5252)
N N CH 3
H
OH CN
N N CH 3
Bz
OBz CN
1
2
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. 106-107.5o C, yield 1.31 g (85%).
5.2.4 特戊酰基保护羟基示例
(J.Am.Chem.Soc . 1980,102,7962)
3
3
1
2
The triol 1 (3.24 g, 20 mmol) is dissolved in pyridine (20 mL) and dry didhloromethane (20 mL) is added. To the cold (0o C) 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%).
5.2.5 乙酸酯脱保护示例 (J.Am.Chem.Soc. 1972,94,8613)
2CH 3
2CH 3K 2CO 3/MeOH
1
2
A mixture of 1 (1.59 g, 6.0 mmol) and K 2CO 3 (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 CH 2Cl 2 (25 mL 3). The extract was dried over MgSO 4 and concentrated in vacuo to afford 2 1.13 g (85%).
5.2.6 苯甲酸酯脱保示例( .Chem. 1981, 46, 5252)
N N CH 3
Bz
OBz CN
N N CH 3
Bz
OH CN
1
2
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%).
5.2.7 特戊酸酯脱保护示例(J.Am.Chem.Soc . 1990,112,3693)
A PvO
N 3
OMs A HO
H 2N
OMs
1
21.Pd/BaCO ,2.NaOMe/MeOH
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/BaCO 3 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/H 2O, 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.
The End。