Stereoselective Synthesis of (R)-glycidyl Butyrate
Letters in Organic Chemistry, 2011, Vol. 8, No. 4 243
yield. Finally, the ee value of (R)-glycidyl butyrate reachs
resolution of epichlorohydrin first. Further application of this
methodology to the synthesis of all the similar targets should
be taken into account.
9
0%, the yield of 40% is obtained.
In order to achieve the synthesis of target molecule, we
can get chiral epichlorohydrin by hydrolytic kinetic
resolution epichlorohydrin directly (Scheme 2).
ACKNOWLEDGMENT
OH
Cl
Cl
Cl
The
authors
thank
Zhejiang
Neo-Dankong
O
O
O
a
Cl
OH
Pharmaceutical Co., Ltd. for the financial support.
+
4
5
O
OH
REFERENCES AND NOTES
b
+
O
Cl
O
[1]
Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.; Manninen,
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Wu, D. R.; Cramer, S. M.; Belfort, G. Kinetic resolution of racemic
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A two-step enzymatic resolution of glycidyl butyrate. Process
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Pandey, S. K.; Pandey, M.; Kumar, P. A concise synthesis of
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4
4
6
7
OH
O
c
O
O
8
[2]
[3]
[4]
Scheme 2. Reagents and conditions: (a) (R,R)-salen-Co-(OAc) (0.5
mol%), dist. H O (0.55equiv), 0 °C, 1 2h, (45% for 4, 43% for 5;
b) CrCl , 60 °C, 24 h, 95%; (c) NaOH, reflux, 12 h, 90%.
2
(
3
Scheme 2 presents the synthesis of intermediates with
a key
hydrolytic kinetic resolution epichlorohydrin first. It is easy
to get the corresponding enantiomeric pure (S)-
epichlorohydrin in 43% yield and 99% optical purity by
distillation at reduced pressure, along with the separable diol
with the yield of 47% (the boiling point of epichlorohydrin is
15-117 ºC and the boiling point of (R)-3-chloropropane-
,2-diol is 213 ºC). The overall yield of the epichlorohydrin
is typically 40–45%. Additional 4–5% of epichlorohydrin
remains in the pot, which could be recovered by utilizing
lower vacuum distillation. The epichlorohydrin shows no
loss of enantiomeric excess, and the purity is more than 99%
by GC analysis.
1
1
[5]
[
6]
7]
[
9(20), 3297-3299.
[
8]
9]
Naidu, S. V.; Kumar, P. Enantioselective synthesis of (ꢀ)-pinellic
acid. Tetrahedron Lett., 2007, 48(13), 3793-3793.
Raj, I. V, P.; Sudalai, A. Asymmetric synthesis of (S)-vigabatrin
With the enatiomerically pure epoxide in hand, our next
aim is to react (S)-epichlorohydrin with butyric acid, in the
®
[
presence of Cr(ꢀ) as catalyst. Several catalysts are chosen
and (S)-dihydrokavain via cobalt catalyzed hydrolytic kinetic
resolution of epoxides.Tetrahedron Lett., 2008, 49(16), 2646-2648.
Kumar, P.; Naidu, V.; Gupta, P. Application of hydrolytic kinetic
resolution (HKR) in the synthesis of bioactive compounds.
3 3 3 3
for the reaction, such as CrCl , Cr(NO ) and Cr(OH) . It is
[
10]
11]
found that CrCl is the best one for this kind reaction with the
3
yield of 95%. Then the compound was subjected to NaOH
Tetrahedron, 2007, 63(13), 2745-2785.
1
[
Spectral data of compound 7. H NMR (500MHz, CDCl
3
): ꢁ 4.03-
epoxidation, which provides the target compound (R)-
4
.03 (m, 2H), 3.92-3.90 (m, 1H), 3.75 (-OH, 1H), 3.47-3.41 (m,
25
glycidyl butyrate in 90% yield, [ꢀ] =30º (c=neat). The
13
D
2H), 2.19-2.16 (m, 2H), 1.51-1.46 (m, 2H), 0.80-0.77 (m, 3H);
NMR (500MHz, CDCl ): ꢁ 173.0, 68.9, 68.4, 47.7 , 36.0, 18.5,
3.5. Anal. Calcd for C (180.5): C, 46.55; H, 7.25%.
Found: C, 46.55; H,7.25%. Spectral data of compound 8. H NMR
500MHz, CDCl ): ꢁ 4.19-4.16 (d, 2H), 3.68-3.64 (m, 1H), 2.60-
.40 (d, 2H), 2.12-2.09 (m, 2H), 1.45-1.41 (m, 2H), 0.74-0.71 (m,
C
physical and spectroscopic data of (S)-3-chloro-2-
hydroxypropyl butyrate (7) and (R)-glycidyl butyrate (8) are
3
1
7 3
H13ClO
1
1
13
determined by H NMR and C NMR [11].
(
3
2
3
1
In conclusion, two efficient strategies amenable to the
synthesis of (R)-glycidyl butyrate are discussed. The desired
stereocenter can simply be achieved by changing the
hydrolytic kinetic resolution step. In the view of separation
problem, it is a better choice to obtain the product via kinetic
13
H); C NMR (500MHz, CDCl
8.4, 13.6. Anal. Calcd for C17
3
): ꢁ 173.0, 67.0, 49.3, 44.0, 36.1,
(144): C, 58.32; H, 8.39%.
12 3
H O
Found: C, 58.31; H, 8.40%.