Bull. Chem. Soc. Jpn., 78, No. 3 (2005)
Ó 2005 The Chemical Society of Japan
499
Table 2.
LiOH
5/%
NaOH
Reaction time/min
4/%
Ratio 4:5
4/%
5/%
Ratio 4:5
2
2
3
3
0
5
0
5
66.2
61.1
59.2
55.9
33.8
38.9
40.8
44.1
1.96
1.57
1.45
1.27
67.8
67.4
61.4
60.9
32.2
32.6
38.6
39.1
2.11
2.07
1.59
1.56
KOH
CsOH
Reaction time/min
4/%
5/%
Ratio 4:5
4/%
5/%
Ratio 4:5
1
1
2
2
0
5
0
5
86.8
74.5
69.0
67.9
13.2
25.5
31.0
32.1
6.58
2.92
2.23
2.12
82.2
67.8
64.6
51.9
17.8
32.2
35.4
48.1
4.62
2.11
1.82
1.08
The boxes indicate the point at which the starting diester 3 has been consumed.
with LiOH or NaOH, the starting diester was consumed after
0 min, at which stage the selectivities showed comparable re-
Experimental
2
The typical procedure for monohydrolysis of diester 3 is as fol-
lows: Diester 3 (213 mg, 1.33 mmol) was dissolved in 2.2 mL of
THF, and 22.2 mL of water was added. The reaction mixture was
sults. However, when the same monohydrolosis was performed
with KOH and CsOH, the starting diester was consumed with-
in a shorter period of time (ca. 10 min), indicating enhanced
reactivity, as in the case of the monohydrolysis of 1.
ꢂ
cooled to 0 C by being immersed in an ice-water bath. To this
reaction mixture was added 8.9 mL of a 0.25 M aqueous solution
of the inorganic base dropwise with stirring. The reaction mixture
was stirred for the indicated period of time, and acidified with 1 M
Interestingly, the selectivity for forming the half-ester was
also enhanced when KOH or CsOH was applied, as opposed
to what would be expected from the general tendency. The se-
lectivity was particularly high when KOH was applied. This
order is about the same as the reactivity observed above;
namely, the selectivity to form predominantly the half-ester
is K > Cs > Na ꢁ Li, which is roughly consonant with the
reactivity. The differences in the selectivity are particularly
prominent at the stage when the starting diester, 3, has just
been consumed (the top row for each base, within the box).
As expected, the yield of the half-ester, 4, decreased, with
more diacid, 5, being formed as the time passed in all the
cases, although after the first 5–10 min of the starting diester’s
being consumed, dramatic change in the ratio 4:5 was not
observed in any of the cases.
ꢂ
HCl at 0 C, saturated with NaCl, extracted with ethyl acetate four
to five times, and dried with magnesium sulfate. When the starting
1
diester, 3, was consumed, the H NMR spectra of the concentrated
residues of these extracts were used to determine the ratios of the
products from the relative intensities of the integral curves of the
methyl and methylene signals.
This work is supported by the National Science Foundation-
CAREER (CHE-0239527). S. N. thanks Banyu Pharmaceuti-
cal Co. Ltd. for the Banyu Award in Synthetic Organic Chem-
istry.
References
These selectivities are also roughly correlated to the electro-
positive character of the counter cations (Cs ꢁ K > Na ꢁ
1
For example, a) S. Sano, H. Ushirogochi, K. Morimoto, S.
9
Tamai, and Y. Nagao, Chem. Commun., 1996, 1775. b) M. S. Yu,
I. Lantos, Z.-Q. Peng, J. Yu, and T. J. Cacchio, Tetrahedron Lett.,
Li). Therefore it is possible to assume that counter cations
are participating in the initial stage of the reaction where the
discrimination is about to occur in order to bring the two iden-
tical ester groups into close proximity by electrostatic effects.
These electrostatic effects should play a more important role
in such ‘‘free’’ acyclic systems than in rigid cyclic systems.
The enhanced size and ‘‘softness’’ of the counter cations are
also expected to provide advantages for the affinity in general.
The somewhat reversed selectiviy between potassium and
cesium cations may be attributed to the increased size and
softness of the Cs cation, which is likely to make the coordi-
nation with the hard oxygen rather looser than the harder
4
1, 5647 (2000). c) S. Kobayashi, K. Kamiyama, and M. Ohno,
J. Org. Chem., 55, 1169 (1990). d) K. Drauz and H. Waldmann,
‘Enzyme Catalysis in Organic Synthesis,’’ VCH Publishers,
Weinheim, New York (1995), pp. 165–261.
For example, a) C. H. Wong and G. M. Whitesides,
‘Enzymes in Synthetic Organic Chemistry,’’ in ‘‘Tetrahedron
Organic Chemistry Series,’’ Pergamon Press, Oxford, New York
‘
2
‘
(
(
1994), Vol. 12. b) M. Ohno and M. Otsuka, Org. React., 37, 1
1989). c) E. Schoffers, A. Golebiowski, and C. R. Johnson,
Tetrahedron, 56, 3769 (1996). d) R. Ozegowski, A. Kunath, and
H. Schick, Tetrahedron: Asymmetry, 6, 1191 (1995). e) K.
Yamamoto, T. Nishioka, J. Oda, and Y. Yamamoto, Tetrahedron
Lett., 29, 1717 (1988).
þ
cation, K .
In summary, we found that several counter cations can con-
trol the selectivities in monohydrolyses of acyclic symmetric
diesters. As opposed to the generally expected tendencies,
more reactive bases showed higher selectivities, with KOH
yielding the highest selectivity. Primary factors are likely to
be attributed to the electropositive character and size of the
counter cations.
3
Non-enzymatic methods for production of half-esters are
more common from cyclic anhydrides. For example, a) A. C.
Spivey and B. I. Andrews, Angew. Chem., Int. Ed., 40, 3131
(2001). b) R. S. Ward, Chem. Soc. Rev., 19, 1 (1990). c) M. C.
Willis, J. Chem. Soc., Perkin Trans. 1, 1999, 1765. d) G. Jaeschke
and D. Seebach, J. Org. Chem., 63, 1190 (1998). e) J. Hiratake, M.