Acetol: a useful new protecting group for peptide synthesis

Tetrahe&on Letters, Vol. 33, No. 22, pp. 3193-3196, 1992 Printed in Great Britain

0040-4039/92 $5.00 + .00 Pergamon Press Ltd

A C E T O L : A U S E F U L NEW P R O T E C T I N G G R O U P F O R P E P T I D E S Y N T H E S 5 + BiJoy

Kundu

Division of B i o p o l y m e r s Central Drug R e s e a r c h Institute, L u c k n o w 226 001,

India

: Acetol can be conveniently used as a reagent for the protection of carboxylic acids in peptide synthesis. It has been found to be inert and stable to h y d r o g e n o l y t i c and acidolytic conditions normally used in peptide synthesis. Deblocking has been selectively achieved under mild conditions using Bu4NF.3H20 in THF.

ABSTRACT

One protect

of

the

essential

the carboxyl

group

which

in

other

sensitive

requirements

turn

can

features

be of

selectively peptides I.

reported

in the l i t e r a t u r e w h i c h

the

of

use

often

strong

limit

aromatic either

due

acid

their

esters

or

scope.

avoids

to

their

new

carboxyl

Use

There

synthesis

groups

affecting

variety

of

problems

sulphur

This

has

from

cleavage

substituted often

arise

containing

necessiated

the

esters

However,

ester

hydrogenolysed

with

both

a

affect

however,

reactions.

protecting

to

of ~ readily

incompatibility

without

are

is to

protecting

for this purpose.

necessary

difficulty,

side

removed

are envisaged

bases

the

acid or due to undesired for

during peptide

function of an amino acid with a suitable

point

a

of

amino search

view

of

selectivity and stability. In group the

the

first

have

been acetol

yields.

The

group

using

the

ester which was found due

to

partial

ethylphenyl

The

+ CDRI Communication No.

amino

found

is

synthesis in the

deblocking 4941

3193

the

to

were

acetolyl

esterified quantitative

to

acidolytic 4 conditions of

analogous

during

carbonyl ester

In

esters

Pd-C)

removal

the

cleaved

phenacyl

acetolyl

stable (H 2,

protecting

described.

essentially

be

for

is

acids

in

to

contrast

of

carboxyl acid

amino

incompletely of

new

hydrogenolytic B

peptide

to be

a

synthesis

procedure 2

were

and

This

reduction

ester 6.

N-protected

esters 3

respectively.

of

peptide

N-protected

DCC/DMAP

TFA/CH2CI 2) in

to

The

the

acetolyl

used

application

several

synthesised.

(HC1/dioxane, routinely

paper

(CH3COCH2OH)

instance,

with

Z

present

: acetol

BOC

and

phenacyl

hydrogenolysis

giving can

rise be

to

carried

3194

Z/Boc-Aaa-0H

+

HOCH2COCH 3 DCC/DMAP

Z/Boc-Aaa-OCH2COCH 3 Bu4NF.3H20/THF Z/Boc-Aaa-OH

Aaa = Amino acid out

under

very

mild

and

in THFat room

temperature

widely

as

used

phase peptide

a

good

simple

a

and

utility

of

by

Further,

the

Leu-enkephalin 9. for

enkephalin

the

cleavage

selective

in of

possibility

of

crude

and

c0mplete

The reaction

of

has

of

the of

Bzl

solid within

generates

product the

peptide a

and t-Bu

by

racemisation

synthesis

biologically

enkephalin

analysed

Yield %

groups

obtained

reverse and

no

has

active

been penta-

after

Bu4NF

phase

h.p.l.c,

trace

of

m.p. °C

[~]D(CHCl 3 )

FABMS (M+H)

91

51

-24.9(c,I.8)

308.1

Boc-Val-OAce

85

59

-34.6(C,i.2)

274.1 266.1

Z-Gly-OAce

92

66

Boc-Thr(Bzl)-OAce

85

oil

-7.8(C,I.0)

366.1

Boc-Leu-OAce

83

oil

-26.5(c,i.i)

287.I

Boc-Asp(OBzl)-OAce

80

oll

+13.5(c,i.i)

380.i

Z-Asp(O-t-Bu)-OAoe

84

85-87

+15.3(c,i.0)

380.1

Boc-Pro-OAce

89

oil

-39.3(c,i.0)

272.1

Boc-Phe-Leu-OAce

85*

97-99

-25.0(c,0.9)

435.2

Z-Gly-Phe-Leu-OAce

77*

91-92

-23.3(C,1.2)

526.3

Z-Gly-Gly-Phe-Leu-OAce

69*

80-82

-15.8(c,i.4)

583.3

BocTyr-Gly-Gly-Phe-Leu-OAce

68*

67-69

-29.2(c,i.i)

723.3

from peptide

couplin E reaction

to

D-Leu-

Z-Val-OAce

*Yields

was

acetolyl

could be detected.

Compounds

been

for COOH and OH functions.

esters

The

Bu4NF.3H20

solution was

removal

presence

synthesis

was

in

using

Bu4NF.3H20

purification

out even in the

acetolyl

both

deblocking

any side reaction.

hence

successful

acidolytic

check

and

conditions yields 7.

reagent

used as side chain protection

The

and

without

convenient.

demonstrated peptlde

cleavage

byproduct

group could be carried generally

neutral

quantitative

synthesis 8. In most cases

5-45 mln and proceeded acetol as

nearly in

3195

These masking

result

of

show

carboxyl

ion final

that

deprotection

protection

scheme

General procedure

acetol

strategy

may

make

was

stirred

based

it a

for

1 hr

at

added

O°C

and

DCC

then

DCU was filtered

at room temperature. washed

successively with

evaporated

to

with

brine.

5%

dryness.

from EtOAc/Hexane chromatography

aq.

The The

or purified

for

and

the

crude

product

at

room

temperature.

After

taken

by

under

reduced with

organic

pressure.

5%

layer

aq

:

A

solution 2-4

(1.0 M,

residue

dried

aq

NaHC03

Na2S04

and

crystallised

silica

of

peptide

equivalents)

of

was

KHS04 'several times

was

5%

evapo-

in EtOAc,

gel

column

(1:2) as an eluant.

completion

The

stirring

up

either

was

amount

Reaction

was

over

reaction

over. Na2S04

then and

and

by

concentrated

dissolved

in EtOAc

with

evaporated

in

stirring

monitored

and

finally

esters

under

as

t.1.c., the reaction was quenched by adding cold water washed

O°C.

overnight

dried

necessary

suitably

catalytic

water,

was

choice.

of

at

the

orthogonal

filtrate

then

acid,

layer

General procedure for deblocking THF was treated with Bu4NF/THF

was

citric

wherever

and

left

off

organic

using EtOAc-Hexane

solution

a

for

fluoride

its

better

of

(1.1 mmol)

rated under reduced pressure. The residue and finally

group

To

and

dimensional

two

(1.2 mmol)

acetol

was

in CH2C12

synthesis

on

:

suited

ideally

be

protecting

for esterification

protected amino acid (1 mmol), of DMAP (5 mgs)

will

in peptide

functions

to

brine.

and The

dryness

to

get required acid in excellent yield. Acknowledgement

:

The

author

is

grateful

to Dr.

K.B.

Mathur

for

his

keen interest in this work. References and Notes 1.

Gross, E. and Meienhofer,

J. in The Peptides,

3,

p

102,

Academic

Press, New York (1981). 2.

Dhaon,

M.K.,

Olsen,

R.K.

and

Ramasamy,

K.,

J. Org. Chem.,

47,

1962 (1982). 3.

All

N-protected

amino

acid

acetolyl

esters

gave

satisfactory

'H-NMR. 4.

Z-Val-OAce

(100 mg)

and 4N HCl/dioxane of

the

solvent,

was

treated

separately

with

TFA/CH2C12

for 1 hr at room temperature. After Z-Val-OAce

was

recovered

in

evaporation

quantitative

thereby suggesting stability of -0Ace to acidolytic

(1:l) yield

conditions.

.

3196

Boc-Val-0Ace to

usual

work

suggesting 6.

hydrogenation up

Taylor-Papadimitriou,

The

were

56, 5464 9.

amino

(i0

Pd-C

recovered carbonyl

ml)

for

and 20

subjected

hPs.

in quantitative

After yields

to hydrogenolysis.

C.,

Poganou,

A.

and

Zervas,

(1967). acids

obtained

by

after

comparing

removal

with

of

authentic

-0Ace sample

rotation and IH NMR.

M.,

Kundu,

(1991) and ref.

Leu-enkephalin

B.

and

procedures.

by active ester

(Received in UK 19 March 1992)

Rinehart,

K.L.,

J. 0rg.

Chem.,

therein.

was synthesised

and mixed anhydride peptlde

was

in Me0H 10%

Yovanidis,

characterised

using optical Namikoshi,

J.,

Soc. C 1830

N-protected

groups

8.

Boc-Val-0Ace

using

stability of acetolyl

L. J. Chem. 7.

(200 mg) was dissolved

catalytic

in a stepwlse manner Boc-Tyr was

(pentafluorophenyl)

coupled method.

using to

DCC/HOBt

the

tetra-