1. Recent Progress of Selective Monohydrolysis of Symmetric Diesters
Satomi Niwayama
Graduate School of Engineering
Muroran Institute of Technology

2. Synthesis of Pharmaceuticals with the use of half-esters

3. Previous examples of monosaponification
KOH C 6 H 5
COOC 2 H 5
EtOH C 6 H 5
COOC 2 H 5
Vecchi, A.; Melone, G. H 3 C
COOC 2 H 5
r.t. 100hrs H 3 C
COOH
J. Org. Chem.
1959 , 24
109
(yield unknown)
KOH
COOC 2 H 5
EtOH
COOC 2 H 5
Corey, E. J. Pr Pr
J. Am. Chem. Soc.
1952 , 74
, 5897
COOC 2 H 5
r.t. 20
hrs
COO H
74.6 %
KOH
COOC 2 H 5
EtOH
COOC 2 H 5
Corey, E. J. C 6 H 5 C 6 H 5
COOC 2 H 5
r.t. 1 .5
hrs
J. Am. Chem. Soc.
1952 , 74
, 5897
COO H
98.5 % (as a crude product)

4. New Selective Monohydrolysis
aqueous NaOH or KOH CO 2 R
THF or other co-solvent CO 2 H o C H 3 O + CO 2 R CO 2 R
R=Me, Et

5. Comparison to C lassical onditions NaOH/MeOH (1eq.) 10% y ellowish2 Me H
NaOH/MeOH
(1eq.)
10% y
ellowish
r.t.
+ diester
+ dicarboxylic acid CO 2 Me H
THF/aqueous NaOH
(2eq.) o
C, min.
~quant.
white cryst.
m.p
C (lit C)

6. Monohydrolysis of Symmetric Diesters
MeO 2 C CO Me H O
>99%
95% b
79% 1a 5 HO 1b 2b
entry 1 3 5a
70% 2a 4
diester
product
yield (%) a 4b 3b 3a 5b 4a 6 6a 6b CH Ph 7 7a 7b 8 8a 8b
96% 9 9a 9b
Yields are isolated yields from silica gel column chromatography based on the
amounts of the diesters submitted to the reaction.
The yield was diminished due to the slight volatility of .

7. Potential Mechanism H2O H2O H2O H2O H2O H2OCO 2 R - O C RO
H2O
H2O
H2O
H2O
H2O
Soap-like aggregates prohibit further hydrolysis

9. Solvent Effects

10. Effects of Kinds of Co-Solvent

11. A B or Nu Conformational Preference of the Starting Diesters d + - O H
OMe R Me
CHO CO 2
SnBu 3 d +
anti-Cram
a) high pressure or - Nu
MeO
Cram
82-90
18-10 :
J. Am. Chem. Soc.
1990 ,
112
, 8598 A B
heating or BF .
OEt
b) i) BF
ii) H
, Pd/C
Yamamoto, Y.
; Nemoto, H.; Kikuchi, R.;
Komatsu, H.; Suzuki, I. H

12. The Conformer of Dimethyl Maleate with the Lowest Energy
(MP2/6-31G(d)//B3LYP/6-31G(d))
72.6o
7.4o
2.850Å
111.2o
8.3o
dihedral angles
n->* interaction

13. Experimental Support for the Predominant Conformation by Theoretical Studies

15. 6 . 5 8 2 9 3 1 4 7 K O H C s L i N a r S l v y > ≥ E p h R e c t o7 K O H C s L i N a R e c t o n m / r : b ( % ) q u M T F , = + d S l v y
> ≥ E p h

16. New Conditions for Monohydrolysis of Linear Diesters
100g $306
~96% purity
~100% purity
More hydrophobic

19. Recognition of Steric Environment
0 oC
0 oC

20. Summary A highly efficient, mild, straightforward reaction using
co-solvent
aqueous base CO 2 R CO 2 H o C H 3 O + CO 2 R CO 2 R
R=Me, Et
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.
This reaction has been licensed by Kishida Chemical Co.Ltd., Japan