氨基的保护及脱保护

Boc

和

Cbz

同时存在时，

可以用催化氢解脱去

Cbz

，

Boc

保持不变，

或用酸解脱去

Boc

而

Cbz

不受影响，因而两者能很好地搭配。

2.1.1

叔丁氧羰基的导入

游离氨基在用

NaOH

或

3

控制的碱 性条件下用二氧六环和水的混合溶剂中很

容易同

Boc

2

O

反应得到

N-

叔丁氧羰基氨基化合物

[1]

。

Boc

常用方法之一，

< br>它的

优点是其副产物无多大干扰并容易除去。有时对一些亲核性较大的胺，一般可 在甲醇

中和

Boc

酸酐直接反应即可， 无须其他的碱，其处理也方便。

对水较为敏感的氨基衍生物，

采用

Boc

2

O/TEA/MeOH

or

DMF

在

40-50

℃下进行较好，

因为这 些无水条件下用于保护

O

17

标记的氨 基酸而不会由于与水交换使

O

17

丢失

[2]

。

有空

间位阻的氨基酸而言，用

Boc

2

O/ CH

3

CN

是十分有利的。

1.

D. S. Tarbell, Y. Yamamoto et al.,

Proc. Natl. Acad. Sci., USA

,

1972

,

69

,

730

2.

E. Ponnusamy, U. Fotadar et al.,

Synthesis.,

1986

, 48

< br>芳香胺由于其亲核性较弱，一般反应需要加入催化剂，另外对于伯胺，通过

DMA P

的使用可以上两个

Boc.

对于有 酚羟基存在的胺，酚羟基上接

Boc

的速度也是相当快的，因而 一般没太大

的选择性。

对于有醇羟基 存在的，若用

DMAP

做催化剂，时间长了以后醇羟基也能上< /p>

Boc

，

因此反应尽量不要过夜。

由于氰酸酯 的生成，

有位阻的胺往往会与

Boc

2

O

生成脲

[1]

。

这个问题可通过该胺

NaH

或

NaHMDS

反应，然后再与

Boc

2

O

反应来加以避免

[2]

。

1.

H.

J.

knolker,

T.

Braxmeier

et

al.,

Angew.

Chem.,

Int.

Ed.

Engl.,

1995

,

34

,

2497;

H.

J.

knolker,

T.

Braxmeier

et

al.,

Synlett.,

1996

,

502;

Kessier,A.;

Coleman, C. M., et al

J. Org. Chem

.,

2004

,

69(23)

, 7836-7846

2.

T. A. Kelly, D. W. McNeil.,

Tetrahedron Lett.,

1994

,

35

, 9003

< br>有时在反应中有可能多加了

Boc

酸酐，当分子中无游离 酸碱时很难出去，若一定

要除去，一般在体系中加入一些

N,N -

二甲基乙二胺或

N,N-

二甲基丙二 胺，而后将上了

Boc

的

N,N-

二甲基乙二胺或

N,N-

二甲基丙二胺用稀 酸除去。

由于

Boc

对酸敏感，因此在合成过程中用到酸洗或酸溶解等操作时，为了保险起

见，尽量 不用盐酸而用

10%

柠檬酸（

0.5M

）或在低温条件进行。

2.2.1.1

氨基酸

Boc

保护示例

Oskar Keller, Walter E. Keller, Gert van Look et al.,

Org. Syn.,

63

, 160

A

4-L,

four- necked,

round-bottomed

flask,

equipped

with

an

efficient

stirrer,

a

dropping

funnel,

reflux

condenser,

and

thermometer

is

charged

with

a

solution

of 44 g mol) of

sodium hydroxide in

1.1

L of water. Stirring

is initiated and

165.2 g (1 mol) of L-phenylalanine is added at ambient temperature, and then

diluted

with

750

mL

of

tert

-butyl

alcohol.

To

the

well-stirred,

clear

solution

is added dropwise within 1 hr, 223 g (1 mol) of di-

tert

-butyl dicarbonate. A

white precipitate appears during addition of the di-

tert

-butyl dicarbonate.

After a short induction period, the temperature rises to about 30

–35°C. The

reaction

is

brought

to

completion

by

further

stirring

overnight

at

room

temperature. At this time, the clear solution will have reached a pH of

–

.

The reaction mixture is extracted two times with 250 mL of pentane, and the

organic

phase

is

extracted

three

times

with

100

mL

of

saturated

aqueous

sodium

bicarbonate solution. The combined aqueous layers are acidified to pH 1

–

by

careful addition of a solution of 224 g mol) of potassium hydrogen sulfate

in 1.5 L of water. The acidification is accompanied by copious evolution of

carbon

dioxide.

The

turbid

reaction

mixture

is

then

extracted

with

four

400-mL

portions

of

ethyl

ether.

The

combined

organic

layers

are

washed

two

times

with

200

mL

of

water,

dried

over

anhydrous

sodium

sulfate

or

magnesium

sulfate,

and

filtered.

The

solvent

is

removed

under

reduced

pressure

using

a

rotary

evaporator

at a bath temperature not exceeding 30°C. The yellowish oil that

remains

is

treated

with

150

mL

of

hexane

and

allowed

to

stand

overnight.

Within

1

day

the

following

portions

of

hexane

are

added

with

stirring

to

the

partially

crystallized product: 2 × 50 mL, 4 × 100 mL, and 1 × 200 mL

. The solution

is placed in a refrigerator overnight; the white precipitate is collected on

a

Büchner

funnel

and

washed

with

cold

pentane.

The

solid

is

dried

under

reduced

pressure at ambient temperature to constant weight to give a first crop. The

mother

liquor

is

evaporated

to

dryness

leaving

a

yellowish

oil,

which

is

treated

in the same manner as described above, giving a second crop. The total yield

of pure white

N-tert

-butoxycarbonyl-L- phenylalanine is 207

–

230 g (78

–

87%),

mp 86

–88°C

,

[α]

D

20

+ °

(ethanol

c

.

2.2.1.2

Boc

保护示例

Alessandro Dondoni, Daniela Perrone.,

Org. Syn.,

77

, 64

A 500-mL, three-necked, round-bottomed flask, is equipped with a magnetic

stirring

bar,

thermometer,

reflux

condenser

protected

from

moisture

by

a

calcium

chloride-filled

drying

tube,

and

a

pressure-equalizing

dropping

funnel

that is connected to a nitrogen flow line and is charged with a solution of

97% di-tert-butyl dicarbonate (14.3 g, mmol) in tetrahydrofuran (100 mL),

Methyl serinate hydrochloride (10.0 g, mmol) is placed in the flask and

suspended

in

tetrahydrofuran

(200

mL)

and

99%

triethylamine

(14.0

g,

138

mmol).

The

resulting

white

suspension

is

cooled

with

an

ice-water

bath

and

the

solution

of di-tert-butyl dicarbonate is added dropwise over a period of 1 hr. After

10

min

of

additional

stirring,

the

ice-water

bath

is

removed

and

the

suspension

is stirred

overnight (14 hr) at room temperature, then warmed at 50°C for a

further 3 hr. The solvent is removed under reduced pressure and the residue

is

partitioned

between

diethyl

ether

(200

mL)

and

saturated

aqueous

bicarbonate

solution (250 mL). The aqueous phase is extracted with three 150-mL portions

of diethyl ether. The combined organic phases are dried with anhydrous sodium

sulfate and concentrated under reduced pressure to give -14.0 g (95-99% crude

yield) of N-Boc-L- serine methyl ester as a colorless oil that is used without

further purification.

[α]

D

23

°

(MeOH,

c

.

2.2.1.3 Boc

酸酐在甲醇中与胺直接反应

Boc

2

O

(262

g, mol)

in

MeOH

(250

ml)

was

added

to

a

soluton

of

compound

1

(157.2

g, mol) in MeOH (350 ml) at 10

°C

, and the resulting mixture was stirred at

room temperature for 2 h. N

1

, N

1

-dimethylethane-1,2-diamine (26 g, mol) was

added and the mixture was stirred at room temperature for 15 min. The solvent

was removed in vacuo, and the residue was dissolved with ethyl acetate (750

ml). The combined organics were washed with 1 N HCl (2 x 250 ml) and brine (2

x 250 ml), dried over sodium sulfate and filtered. The solvent was removed to

give compound

2

(250 g, 96%), which was used directly in the next step.

2.2.1.4

芳胺的单

Boc

保护示例

< br>

Luo, Qun-Li; Liu, Zhi-Ying et al.,

J. Med. Chem.,

2003

, 46(13)

, 2631-2640

3-Aminopyridine-2-carboxylic acid (5.02 g, 36 mmol) was suspended in 60 mL of

dry

DMF,

and

Et

3

N mL,

108

mmol)

was

added

dropwise

at

room

temperature.

To

the

resulting

brown

solution

was

added

Boc

2

O

(11.80

g,

54

mmol).

After

being

stirred

for

10

min,

the

mixture

was

heated

at

40-

50

°C

overnight.

The

reaction

mixture

was

poured

into

water

and

was

then

extracted

with

EtOAc

(2

X

50

mL).

The

aqueous

phase

was

acidified

to

pH

4-5

with

2

M

aqueous

HCl

and

then

extracted

with

CH

2

Cl

2

(3 X 50 mL). The combined organic phases were then processed in the usual way

and

chromatographed

(13:1

CHCl

3

/MeOH)

to

yield

the

desired

product

(4.2

g,

49%).

2.2.1.5

芳胺的双

Boc

保护示例

Macleod,

Calim;

Mckieman,

Gordon

J

et

al.,

J.

Org.

Chem.,

2003

,

68(2)

,

387-401

A solution of NaHMDS mL, mmol, 1 M in THF) was added to a solution of the

amine

(2.11

g, mmol)

and

(Boc)2

O

(5.46

g, mmol)

in

THF

(50

mL)

at

0°C

under

nitrogen. The reaction was allowed to warm to rt and stirred for 16 h. After

this time, the reaction was poured into water, extracted into CH

2

Cl

2

(2 X 25

mL),

washed

with

water

(2

X

25

mL),

dried

over

Na2SO4,

and

concentrated

to

yield

a white-yellow solid. Recrystalization from petroleum ether (40-

60 °C) gave

the imide

as needles

(3.21 g, mmol, 78%).

Rf

(hexane/ CH

2

Cl

2

1:9, SiO

2

): . Mp:

106-

109 °C.

2.2.1.6

酰胺的

Boc

保护示例

Lars G. J. Hammarstr?m, Yanwen Fu et al.,

Org. Syn.,

81

, 213

A 2000-mL, three-necked, round-bottomed flask equipped with an argon inlet

adapter, glass stopper, and an overhead mechanical stirrer is charged with a

suspension

of

the

hydantoin

1

(26.0

g,

154

mmol)

in

1000

mL

of

1,2-dimethoxyethane.

Triethylamine

(15.7

g,

154

mmol)

is

added

in

one

portion,

and

the

resulting

white

suspension

is

stirred

for

30

min.

Di-tert- butyl

dicarbonate

(168.0

g,

770

mmol)

is

then

added

by

pipette,

followed

by

4-dimethylaminopyridine (DMAP) (0.2 g, mmol). Six additional 0.2 g-portions

of DMAP are added at 12 hr intervals during the course of the reaction. The

reaction

mixture

is

stirred

vigorously

for

a

total

of

72

hr,

and

the

resulting

light

yellow

solid

is

then

collected

in

a

Büchner

funnel

using

suction

filtration.

The

filtrate

is

concentrated

to

a

volume

of

60

mL

by

rotary

evaporation, and the resulting solution is cooled to 15°C. The precipitate

which appears is collected using suction filtration, added to the first crop,

and the combined solids are dissolved in 500 mL of chloroform. This solution

is washed with three 200-mL portions of HCl, and the combined aqueous phases

are

extracted

with

100

mL

of

chloroform.

The

combined

organic

layers

are

washed

with 100 mL of saturated aq NaHCO

3

solution and 100 mL of brine, dried over

anhydrous

MgSO

4

,

filtered,

and

concentrated

by

rotary

evaporation.

The

resulting

solid

is

dried

at

room

temperature

at

0.01

mm

for

24

hr.

The

resulting

finely ground light yellow solid is suspended in 400 mL of diethyl ether in

a 1000-mL, round- bottomed

flask

equipped with a magnetic

stirbar,

stirred for

2 hr, and filtered on a Büchner funnel washing with

four 50-mL portions of

diethyl ether

. The product is dried under vacuum (85°C; 0.5 mm) for 24 hr to

give

–

65.3 g (83-90%) of

2

as a ivory-colored solid.

2.2.1.6 < /p>

叠氮还原

Boc

保护示例

Seiki Saito, Kanji Komada, and Toshio Moriwake.,

Org. Syn.,

73

, 184

A 500-mL, single-necked, round-bottomed flask, equipped with a Teflon-coated

stirring

bar,

is

charged

with

a

suspension

of

0.91

g

of

10%

palladium

on

carbon

catalyst

in

100

mL

of

ethyl

acetate.

The

flask

is

connected

to

a

normal

pressure

hydrogenation apparatus and the catalyst is saturated with hydrogen. After

removal of the hydrogen, a solution of 18.2 g mol) of

1

and 20.6 g mol)

di-tert-butyl

dicarbonate

in

80

mL

of

ethyl

acetate

is

added

to

the

suspension

of

catalyst,

a

hydrogen

atmosphere

reestablished,

and

the

suspension

is

stirred

at room temperature under a slight positive pressure of hydrogen for 4

–

6 hr,

The suspension is filtered through a Celite pad, and the pad is rinsed with

several portions of ethyl acetate. The combined ethyl acetate solutions are

concentrated on a rotary evaporator and finally under high vacuum to give a

pale yellow oil that is initially purified by means of a column packed with

silica

gel

(100

g)

using

hexane- ethyl

acetate

(6:1)

as

eluent.

Fractions

containing the product are combined and concentrated on a rotary evaporator

to give 23.3 g of crude

2

as a colorless oil. The oily crude

2

is dissolved

in 70 mL of hexane-ether

(3:1), and the solution is cooled to ?30°C, seeded,

and

kept

overnight

at

that

temperature

(freezer)

to

allow

crystallization.

The

mother

liquor

is

si

phoned

out

while

the

mixture

is

kept

at

?30°C

(

dry

ice-acetone

bath).

The

crystals

are

washed

with

several

portions

of

hexane-ether

(3:1) at ?30°C, then dried under high vacuum to provide –

12.7

g

of

diastereomerically

and

enantiomerically

pure

diethyl

(2S,3R)-2-(N-tert- butoxycarbonyl)amino-3-hydroxysuccinate (

2

) as colorless

prisms, mp 33

–34°C;

.

The combined mother liquor and the hexane

–

ether (3:1)

washings

are

concentrated

on

a

rotary

evaporator

to

give

a

colorless

oil,

which

upon

crystallization

as

above

provides

an

additional

–

3.8

g

of

product

2

.

The

combined yield of crystalline

2

is

–

16.5 g (66

–

73%).

2.2.1.7

吡咯

Boc

保护示例

Wha Chen, E. Kyle Stephenson et al.,

Org. Syn.,

70

, 151

The solution of 2-bromo-1H-pyrrole (9.8 g, mmol) in 40 mL of THF is cooled

to ?

78°C in a dry ice

-acetone bath. The flask is equipped with a magnetic

stirring

bar

and

a

three-way

stopcock

attached

to

a

balloon

filled

with

nitrogen.

To the stirred dark-green solution is added 2.71 g mmol) of triethylamine

followed

immediately

by

addition

of

20.4

g mmol)

of

di- tert-butyl

dicarbonate

and a catalytic amount (ca. 0.1 g) of 4-dimethylaminopyridine. The flask is

evacuated and purged with nitrogen. The mixture is stirred for 8 hr while it

is allowed to warm to room temperature. The solvent is removed under reduced

pressure

at

room

temperature

and

100

mL

of

hexane

is

added

to

the

crude

product,

which

is

washed

with

deionized

water

(3

×

100

mL),

dried

over

sodium

sulfate,

and

concentrated

under

reduced

pressure

at

room

temperature.

The

crude

product

is purified by chromatography on amine-treated neutral silica (270 g) using

hexane as the eluent. The fractions containing the product are identified by

TLC, combined, and concentrated

under

reduced pressure

at room temperature

to

yield

N-tert- Butoxycarbonyl-2-bromopyrrole

as

a

colorless

oil

–

14.7

g,

82

–

89%).

2.2.1.8

吲哚

Boc

保护示例

G. Tong; P. Ruiyan et al.,

J. Org. Chem.,

1997

,

26,

9298

To

a

solution

of

6-methoxy-3-methylindole

(5.0

g,

31

mmol)

in

distilled

acetonitrile

(150

mL)

were

added

di-

tert

butyl

dicarbonate

(7.44

g, mmol)

and

DMAP (0.195 g, mmol). The reaction mixture was stirred at rt for 12 h. The

solvent

was

removed

under

reduced

pressure.

The

residue

was

dissolved

in

CH

2

Cl

2

(100

mL)

and

washed

with

an