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Recent Progress of Selective Monohydrolysis of Symmetric Diesters

Satomi Niwayama Graduate School of Engineering Muroran Institute of Technology

half-ester

half-ester

half-ester

Synthesis of Pharmaceuticals with the use of half-esters

C 6 H 5

H 3 C

COOC 2 H 5

COOC 2 H 5

C 6 H 5

H 3 C

COOC 2 H 5

COOH

C 6 H 5

COOC 2 H 5

COOC 2 H 5

C 6 H 5

COOC 2 H 5

COO H

Pr COOC 2 H 5

COOC 2 H 5

Pr COOC 2 H 5

COO H

KOH

EtOH

r.t. 100hrs

(yield unknown)

Vecchi, A.; Melone, G.

KOH

EtOH

r.t. 1 .5 hrs

Corey, E. J.

98.5 % (as a crude product)

KOH

EtOH

r.t. 20 hrs

74.6 %

Corey, E. J.

J. Am. Chem. Soc. 1952 , 74 , 5897

J. Org. Chem. 1959 , 24 , 109

J. Am. Chem. Soc. 1952 , 74 , 5897

Previous examples of monosaponification

aqueous NaOH or KOH

0 o C H 3 O

+

CO 2 R

CO 2 R

CO 2 H

CO 2 R

R=Me, Et

New Selective Monohydrolysis

THF or other co-solvent

Comparison to C lassical C onditions

CO 2 Me

CO 2 Me

CO 2 H

CO 2 Me

THF/aqueous NaOH (2eq.)

0 o C, 30-60 min.

~quant. white cryst.

m.p. 106-107 o C (lit. 108-109

o C)

CO 2 Me

CO 2 Me

CO 2 H

CO 2 Me

NaOH/MeOH (1eq.)

10%

y ellowish

r.t. + diester + dicarboxylic acid

Monohydrolysis of Symmetric Diesters

MeO 2 C CO 2 Me

MeO 2 C CO 2 Me

MeO 2 C CO 2 Me

CO 2 Me CO 2 Me

CO 2 H CO 2 Me

CO 2 Me CO 2 Me

O CO 2 H

CO 2 Me

O

>99%

95% b

79%

1a

5

HO 2 C CO 2 Me

1b

HO 2 C CO 2 Me

2b

entry

1

2

3

5a

70%

2a

4

diester product yield (%) a

4b

HO 2 C CO 2 Me 3b 3a

5b

4a

>99%

entry diester product yield (%) a

CO 2 Me CO 2 Me

O O CO 2 H

CO 2 Me

O O >99%

6

6a 6b

CO 2 CH 2 CH 3

CO 2 CH 2 CH 3

Ph CO 2 H

CO 2 CH 2 CH 3

Ph 7

7a 7b

CO 2 CH 2 CH 3 CO 2 H CO 2 CH 2 CH 3

8 CO 2 CH 2 CH 3 8a 8b

>99%

96%

CO 2 CH 2 CH 3 CO 2 CH 2 CH 3

O CO 2 H

CO 2 CH 2 CH 3

O 9

9a 9b

>99%

a Yields are isolated yields from silica gel column chromatography based on the amounts of the diesters submitted to the reaction. b The yield was diminished due to the slight volatility of 3b .

CO 2 R

- O 2 C

RO 2 C

CO 2 -

RO 2 C

CO 2 -

CO 2 R

- O 2 C RO 2 C

CO 2 -

RO 2 C CO 2 -

CO 2 R - O 2 C

CO 2 R

CO 2 -

Potential Mechanism

H2O

H2O

H2O

H2O

H2O

H2O

Soap-like aggregates prohibit further hydrolysis

Solvent Effects

Effects of Kinds of Co-Solvent

H

O O

H OMe R

H H

Me

O Me O

H O R

H H

Me

CHO

CO 2 Me H

H

Me

Me H

SnBu 3

O

O

d +

anti-Cram

O

O

a) high pressure +

or

d -

d +

d -

Nu -

d + d -

d +

d -

O

O O OMe

R R

Me

O

O MeO

OMe

R R

Cram

82-90 18-10 : J. Am. Chem. Soc. 1990 , 112 , 8598

d +

A B

d +

d -

d +

Nu -

heating or BF 3

. OEt 2

b) i) BF 3 . OEt 2

ii) H 2 , Pd/C +

Yamamoto, Y. ; Nemoto, H.; Kikuchi, R.; Komatsu, H.; Suzuki, I.

d -

or

d - d +

d -

Conformational Preference of the Starting Diesters

The Conformer of Dimethyl Maleate with the Lowest Energy (MP2/6-31G(d)//B3LYP/6-31G(d))

dihedral angles

7.4o

111.2o 8.3o

72.6o

2.850Å

n->* interaction

Experimental Support for the Predominant Conformation by Theoretical Studies

6 . 5 8

2 . 9 2

2 . 2 3

2 . 1 2

4 . 6 2

2 . 1 1

1 . 8 2

1 . 0 8

1 0

1 5

2 0

2 5

8 6 . 8

7 4 . 5

6 9 . 0

6 7 . 9

1 3 . 2

2 5 . 5

3 1 . 0

3 2 . 1

8 2 . 2

6 7 . 8

6 4 . 6

5 1 . 9

1 7 . 8

3 2 . 2

3 5 . 4

4 8 . 1

1 . 9 6

1 . 5 7

1 . 4 5

2 . 1 1

2 . 0 7

1 . 5 9

2 0

2 5

3 0

6 6 . 2

6 1 . 1

3 3 . 8

3 8 . 9

6 7 . 8

6 7 . 4

6 1 . 4

3 2 . 2

3 2 . 6

3 8 . 6 5 9 . 2 4 0 . 8

3 5 1 . 5 6 6 0 . 9 3 9 . 1 5 5 . 9 4 4 . 1 1 . 2 7

K O H C s O H

L i O H N a O H

R e a c t i o n t i m e / m i n .

r a t i o a : b a ( % ) b ( % ) R e a c t i o n t i m e / m i n .

C O 2 C H 3

C O 2 C H 3

C O 2 C H 3

C O 2 H

C O 2 H

C O 2 H

1 ) a q u e o u s M O H

T H F / H 2 O , 0 o C

M = L i , N a , K , C s

2 ) H 3 O +

+

a b

r a t i o a : b b ( % ) a ( % )

a ( % ) b ( % ) r a t i o a : b r a t i o a : b b ( % ) a ( % )

d i e s t e r c o n s u m e d

d i e s t e r c o n s u m e d

S e l e c t i v i t y : K > C s > N a ≥ L i E l e c t r o p o s i t i v e c h a r a c t e r : C s ≥ K > N a ≥ L i

New Conditions for Monohydrolysis of Linear Diesters

More hydrophobic

100g $306 ~96% purity

~100% purity

Recognition of Steric Environment

0 oC

0 oC

Summary

A highly efficient, mild, straightforward reaction using co-solvent-aqueous base at 0

oC was found to produce pure half-esters from symmetric diesters in high yields.

co-solvent aqueous base

0 o C H 3 O

+

CO 2 R

CO 2 R

CO 2 H

CO 2 R

R=Me, Et

This reaction has been licensed by Kishida Chemical Co.Ltd., Japan www.kishida.co.jp

• Organic Chemistry: Current

Research

• Pharmaceutica Analytica

Acta

• Clinical Pharmacology &

Biopharmaceutics

4th International Conference on

Medicinal Chemistry & Computer Aided Drug Designing

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