常见的羟基的保护与脱保护方法

(1)

(10-100)

(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。

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

(Bu

4

+

:

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

-< /p>

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. .

1996,

61

, 2065)

Compound

1

(3.00g, 4.286mmol) was dissolved in dry DMF (17 mL). To this solution at 0

o

C was

added

imidazole

(874.3

mg,

12.86mmol),

followed

by

TMSCl

(1.63

mL,

12.86

mmol).

After

stirring at 0

o

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 0

o

C with imidazole

(816

mg,

12.00

mmol),

followed

by

chlorodimethylsilane

(1.135g,

12.00mmol).

The

reaction

mixture was stirred for 1h at 0

o

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. .

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

TBSC l

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

TBS OTf

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

10

4

倍。它对碱稳定。 相对来说对酸敏感些。

TBS

醚的生成和断裂

< br>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

< br>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

< br>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

T BS

，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)

The hydroxyl lactone

1

, upon treatment with TBDMSCl (1.2 equiv) and imidazole (2.5

equiv.) in DMF (2 mL/g of

1

) at 35

o

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

( 1987,

52

, 622)

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

0

o

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)

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 22-24

o

C. The solution was stirred for 2 h

and

diluted

with

100

mL

(1:1)

of

Et

2

O/EtOAc

solution.

The

organic

layer

was

separated

and

washed with H

2

O (3

?

100 mL). The water extract was washed with 2:1 Et

2

O/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< /p>

脱

TBS

示例

(

Tetrahedron Lett.

1988,

29

, 6331)

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

T BDPS

保护基

对碱的稳定性比

TBD MS

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

TBDM S

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

2

CO

3

/CH

3

O H

，对

9

M

氨

水、

60

℃、

2h

；对

MeONa

（

cat.

）

/CH

3

OH

、

25

℃、

24h

均稳定。该醚对

80%

乙酸稳定，后者

可用于脱除醚中

TBDMS

HBr

/Ac OH

，

12

℃，

2min

；对

25%~75%

甲酸，

25

℃，

2h~6h

< br>；以及

50%

三氟乙酸，

25< /p>

℃，

15min

稳定。

< br>

2.3.1

通过

TBDPS Cl

进行羟基的叔丁基二甲基硅醚保护示例

(

< br>. Chem

, 1992,

57

, 1722)

To a solution of 1,4-butanediol (5 g, 55 mmol) in CH

2

Cl

2

(10 mL) containing i-Pr

2

NEt

(10

mL)

was

added

t-BDPSiCl

(5

mL,

18

mmol)

dropwise

under

N

2

at

22-24

o

C.

The

solution

was stirred at 22-24

o

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

< br>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。

基碱性水解时比

TBDMS

基或

TBDPS

基稳定。相对于仲羟基，

基对伯羟基有更好的选择性。

2.4.1

通过

TIPSCl

< br>进行羟基的三异丙基硅醚保护示例

(

J. Org. Chem.

1995,

60

, 7796)

To

a

stirred

solution

of

(1)(1.5

g)

in

CH

2

Cl

2

(53

mL)

cooled

to

0

o

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

4

Cl solution (60 mL).

The phase was

separated and the aqueous layer was extracted with CH

2

Cl

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

2

SO

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

< br>，

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

Na

2

CO

3

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（

H

2

，

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（

< br>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

Solvent

THF

Hexanol

Methanol

Toluene

Hexane

Reaction rate(mm H

2

/ min /0.1g cat)

40

25

5

2

6

3.1.1

< br>烷基羟基的苄基醚保护示例

(

Bull. Chem. Soc. Jpn.

1987,

60

, 1529)

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

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

2

CO

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

2

O (80 mL

?

3).

The extract was washed with saturated NaHCO

3

, water and brine successively.

The organic layer

was dried over Na

2

SO

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)

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.)